Treatment of prostate cancer

ABSTRACT

A chemical agent of the diterpene family obtained from a member of the Euphorbiaceae family of plants for use in the treatment of prophylaxis of prostate cancer or a related cancer or condition.

FIELD OF THE INVENTION

[0001] The present invention relates generally to chemical agents usefulin treatment and prophylaxis of prostate cancer or a related cancer orcondition or in the amelioration of symptoms resulting from orfacilitated by prostate cancer or a related cancer or condition in amammalian animal including human or pR₁mate. More particularly, thepresent invention provides a chemical agent of the diterpene familyobtained from a member of the Euphorbiaceae family of plants orbotanical or horticultural relatives thereof or deR₁vatives or chemicalanalogs or chemically synthetic forms of the agents for use in thetreatment or prophylaxis of prostate cancer or a related cancer orcondition or in the amelioration of symptoms resulting from orfacilitated by prostate cancer or a related cancer or condition in amammal and in particular a human. The present invention furthercontemplates a method for the prophylaxis or treatment of a mammaliansubject presenting with prostate cancer or a related cancer or conditionor with symptoms of prostate cancer or a related cancer or condition bytopical or systemic administration of a diterpene obtainable from amember of the Euphorbiaceae family or botanical or horticulturalrelatives thereof or a deR₁vative, chemical analog or chemicallysynthetic form of the agent. The chemical agent of the present inventionmay be in the form of a puR₁fied compound, mixture of compounds, aprecursor form of one or more of the compounds capable of chemicaltransformation into a therapeutically active agent or be in the form ofa chemical fraction, sub-fraction or preparation or extract of theplant. The present invention particularly relates to the treatment ofeither hormone-resistant or hormone-sensitive prostate cancer ormetastatic prostate cancer using a chemical agent or fraction from thesap of Euphorbia peplus. The chemical agents or chemical fractions ofthe present invention may be given alone or in combination with othercancer symptom-ameliorating chemical or physical agents and/or othertherapeutic interventions including interventionist procedures.

BACKGROUND OF TIHE INVENTION

[0002] Bibliographic details of the publications referred to by authorin this specification are collected at the end of the descR₁ption.

[0003] Reference to any pR₁or art in this specification is not, andshould not be taken as, an acknowledgment or any form of suggestion thatthis pR₁or art forms part of the common general knowledge in Australiaor any other country.

[0004] As the most common internal cancer in older men and the seventhmost common cause of death in men of all ages in developed countR₁es,cancer of the prostate is a seR₁ous health problem in terms of drawn-outpersonal suffeR₁ng and premature death not to mention the cost to thehealth care system. The incidence of prostate cancer appears to beincreasing, over and above improved detection rates in recent years(Post et al., 1999). Although many men with cancer of the prostate diefrom other causes, the high incidence results in significant morbidityand death directly from the prostatic tumor. Currently-available therapycarR₁es a significant R₁sk of major side effects, including incontinenceand impotence, and consequently many men are reluctant to accepttreatment at an early stage of the disease. The need to improve thetreatment of prostate cancer is underlined by the existence of over 150clinical tR₁als world wide (Future Oncology, vol. 4, number 3, 1998),including 34 new or modified products(http://www.phrma.org/pdf/charts/cancer99.pdf).

[0005] Hormone-resistant bony secondaR₁es (hrbs) are universally foundin the natural history of advanced prostate cancer and are resistant toall current chemotherapy. They cause severe pain, prolongedhospitalization, pathological fractures, spinal-cord compression andparaplegia, and may be fatal. External beam radiotherapy is the mainstayof palliative treatment. However, it can only be used once for a givenbony secondary. A range of bone-seeking compounds can image prostatecancer metastases (Bushnell et. al., 1999; NorR₁s et al., 1999).Parenteral strontium isotopes have had limited success for treatment buttheir use is limited by their toxicity to the bone narrow, especiallyplatelets. Bisphosphonates (osteoclast inhibitors) may decrease the bonepain in a few cases, but again are generally disappointing and do notincrease life expectancy.

[0006] There is a need, therefore, to develop more effective therapeuticprotocols and more efficacious therapeutic agents to assist in thetreatment of this disease.

[0007] Natural product screening is a term applied to the screening ofnatural environments for bioactive molecules. Particularly sought afterbioactive molecules are those having potential as useful therapeuticagents. Natural environments include plants, microorganisms, coral andmaR₁ne animals. The search for potential therapeutic agents for thetreatment of cancer and infection by pathogenic organisms remains animportant focus.

[0008] The Euphorbiaceae family of plants covers a wide vaR₁ety ofplants including weeds and other types of plants of Euphorbia species.There has been a vaR₁ety of inconclusive reports on the potentialeffects of the sap of these plants on a range of conditions as well aspromoting tumoR₁genesis and causing skin and ocular iuR₁tation.

[0009] The most intensively studied species of this group is Euphorbiapilulifera L (synonyms E. hirta L., E. capitata Lam.), whose commonnames include pill-beaR₁ng spurge, snakeweed, cat's hair, Queenslandasthnma weed and flowery-headed spurge. The plant is widely distR₁butedin tropical countR₁es, including India, and in Northern Australia,including Queensland.

[0010] A recent report descR₁bes selective cytotoxicity of a number oftigliane diterpene esters from the latex of Euphiorbia poisonii, ahighly toxic plant found in Northern NigeR₁a, which is used as a gardenpesticide. One of these compounds has a selective cytotoxicity for thehuman kidney carcinoma cell line A-498 more than 10,000 times greaterthan that of adR₁arnycin (Fatope et al., 1996).

[0011]Euphorbia hirta plants and extracts thereof have been consideredfor a vaR₁ety of purposes, including tumor therapy (European PatentApplication No. 0 330 094), AIDS-related complex and AIDS (HungaR₁anPatent Application No. 208790) and increasing immunity and as ananti-fungoid agent for treatment of open wounds (German PatentApplication No. 4102054).

[0012] Thus, wlile there are isolated reports of anti-cancer activity ofvaR₁ous Euphorbia preparations (see Fatope et al., 1996; Oksuz et al.,1996), not only are the compounds present in at least one Euphorbiaspecies reported to be carcinogenic (Evans and Osman, 1974; StavR₁c andStolz, 1976; Hecker, 1970), but at least one species has a skin-irR₁tantand tumor-promoting effect (Gundidza and Kufa, 1993) and another speciesreduces EBV-specific cellular immunity in Burkitt's lymphoma (Imai,1994).

[0013] In accordance with the present invention, the inventors haveidentified chemical agents and fractions compR₁sing these agents from aplant of the Euphorbiaceae family which are useful in the treatment andprophylaxis of prostate cancer in mammalian and in particular humansubjects.

SUMMARY OF THE INVENTION

[0014] Throughout this specification, unless the context requiresotherwise, the word “compR₁se”, or vaR₁ations such as “compR₁ses”, or“compR₁sing”, will be understood to imply the inclusion of a statedelement or integer or group of elements or integers but not theexclusion of any other element or integer or group of elements orintegers.

[0015] The present invention is predicated in part on the identificationof chemical agents and fractions compR₁sing same from plants of theEuphorbiaceae family and in particular Euphorbia peplus which are usefulin the treatment and prophylaxis of prostate cancer or a related canceror condition. The chemical agents or fractions compR₁sing same areparticularly useful for the treatment or prophylaxis of, or in theamelioration of symptoms associated with, prostate cancer includingmetastatic prostate cancer.

[0016] Accordingly, one aspect of the present invention contemplates amethod for the treatment or prophylaxis of prostate cancer or a relatedcancer or condition in a subject, said method compR₁sing theadministration to said subject of a symptom-ameliorating effectiveamount of a chemical agent obtainable from a plant of the Euphorbiaceaefamily or a deR₁vative or chemical analog thereof which chemical agentis a diterpene selected from compounds of the ingenane, pepluane andjatrophane families and which chemical agent or deR₁vative or chemicalanalog is represented by any one of the general formulae (I)-(V) asdefined herein and wherein said chemical agent or its deR₁vatives orchemical analogs is administered for a time and under conditionssufficient to ameliorate one or more symptoms associated with saidprostate cancer.

[0017] More particularly, the present invention is directed to a methodfor the treatment or prophylaxis of prostate cancer or a related canceror condition in an subject, said method compR₁sing the administration tosaid subject of a symptom-ameliorating effective amount of a chemicalagent obtainable from E. peplus or a deR₁vative or chemical analogthereof which chemical agent is a diterpene selected from compounds ofthe ingenane, pepluane and jatrophane families and which chemical agentor deR₁vative or chemical analog is represented by any one of thegeneral formulae (I)-(V) as defined herein and wherein said chemicalagent or its deR₁vatives or chemical analogs is administered for a timeand under conditions sufficient to ameliorate one or more symptomsassociated with said prostate cancer.

[0018] Another aspect of the present invention contemplates a method forthe immunopotentiation of a subject in the treatment and prophylaxis ofsaid subject for prostate cancer or a related cancer or condition, saidmethod compR₁sing the administration to said subject of asymptom-ameliorating effective amount of a diterpene, or a chemicalfraction compR₁sing same from a plant of the family Euphorbiaceae or adeR₁vative or chemical analog of said diterpene having the structures asdefined herein against prostate cancer cells.

[0019] Yet another aspect of the present invention contemplates a methodfor the treatment or prophylaxis of a subject with prostate cancer or arelated cancer or condition or with the symptoms of prostate cancer,said method compR₁sing the administration to said subject of asymptom-ameliorating effective amount of an angeloyl-substitutedingenane or a chemical fraction or plant extract compR₁sing same.

[0020] Still another aspect of the present invention provides a methodfor the treatment or prophylaxis of a subject with prostate cancer or arelated cancer or condition or with the symptoms of prostate cancer,said method compR₁sing the administration to said subject of asymptom-ameliorating effective amount of one or more ofingenol-3-angelate, 20-deoxy-ingenol-3-angelate and/or20-O-acetyl-ingenol-3-angelate or a deR₁vative thereof or apharmaceutically acceptable salt of these or a chemical fraction orplant extract compR₁sing same.

[0021] Even yet another aspect of the present invention contemplates amethod for the treatment or prophylaxis of prostate cancer or a relatedcancer or condition in a subject, said method compR₁sing thesimultaneous or sequential admistration to said subject of asymptom-ameliorating effective amount of a chemical agent deR₁ved from aplant of the Euphorbiaceae family as hereinbefore descR₁bed togetherwith a therapeutic protocol or a symptom-ameliorating effective amountof another chemical agent or a physical agent.

[0022] A further aspect of the present invention also provides acomposition for treatment and/or prophylaxis of prostate cancer or arelated cancer or condition in a subject, compR₁sing one or morechemical agents of the present invention, together with apharmaceutically acceptable carR₁er and/or diluent, and optionally oneor more other active compounds.

[0023] Yet another aspect of the present invention encompasses the useof one or more chemical agents of the present invention and optionallyone or more other active compounds in the preparation of a medicamentfor the treatment and/or prophylaxis of prostate cancer or a relatedcancer or condition.

BR₁EF DESCR₁PTION OF THE FIGURES

[0024]FIG. 1 is a diagrammatic representation illustrating the selectivetoxicity of E. peplus sap against prostate cancer cell lines, ascompared to normal fibroblasts (NFF). PC-3 and DU145 are hormoneresistant prostate cancer cell lines. LNcap is a hormone-sensitiveprostate cancer cell line.

[0025]FIG. 2 is a graphical representation of the effects of topicaladministration of PEP003 from E. peplus on DU145 tumors in nude mice.

[0026]FIG. 3 is a graphical representation of the effects of topicaladministration of PEP003 from E. peplus on PC-3 tumors in nude mice.

[0027]FIG. 4 is a graphical representation of the effects ofintralesional treatment by PEP003 on PC-3 tumors in nude mice.

[0028]FIG. 5 is a graphical representation of the effects ofintralesional treatment by PEP003 on DU145 tumors in nude mice.

[0029]FIGS. 6A to 6E are graphical representations showing thesynergistic behaviour of angeloyl-substituted ingenanes in combinationwith chemotherapeutic agents on killing DU145 cells.

[0030] Compounds may be referred to in the subject specification by acompound code. These are defined in Table 1 below: TABLE 1 COM- POUNDCODE DESCRIPTION PEP001 Crude sap PEP002 Methanol and ether extract ofE. peplus sap prepared according to Example 7 of PCT/AU98/00656 PEP003Ingenane enriched fraction prepared according to Examples 2 and 4 PEP004Jatrophane/Pepluane enriched fraction prepared according to Example 7 ofPCT/AU98/00656 PEP005 20-deoxy-ingenol-3-angelate PEP006Ingenol-3-angelate PEP008 20-O-acetyl-ingenol-3-angelate PEP009 AcetoneExtract of XAD (water extract) prepared according to Example 2 PEP010Ingenane enriched fraction prepared according to Examples 3 and 4

DETAILED DESCR₁PTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention is predicated in part on the identificationof biologically useful properties of chemical agents and chemicalfractions compR₁sing these agents obtainable from a member of theEuphorbiaceae family of plants or their botanical or horticulturalrelatives. These biologically useful properties include their use in theprophylaxis and/or treatment of prostate cancer including facilitatingpotentiation of the inmmune system or of cells or other components ofthe immune system in the treatment or amelioration of symptomsassociated with prostate cancer.

[0032] Reference to “prostate cancer” includes cancers related theretosuch as at the biochemical, physiological, pharmacological andimmunological levels. Examples of related cancers include prostaticcarcinogenesis, benign prostatic hyperplasia, prostatic intraepithelialcarcinoma, carcinoma of the bladder, adenocarcinoma of the prostate andrenal cell carcinoma. The term “prostate cancer” includes a conditionhaving the characteR₁stics of prostate cancer and includes conditionsassociated with cancers related to prostate cancer.

[0033] The term “treatment” is used in its broadest sense and includesthe prevention of a disease condition as well as facilitating theamelioration of the effects of symptoms of prostate cancer or a relatedcondition.

[0034] The term “prophylaxis” is also used herein in its broadest senseto encompass a reduction in the R₁sk of development of prostate cancer.In certain conditions, an agent may act to treat a subjectprophylactically. Furthermore, the prophylactic administration of anagent may result in the agent becoming involved in the treatment of adisease condition. Use of the terms “treatment” or “prophylaxis” is notto be taken as limiting the intended result which is to reduce theadverse effects of prostate cancer or to potentiate the immune system orcomponents therein to ameliorate the symptoms or R₁sk of development ofsymptoms caused or facilitated by prostate cancer.

[0035] The present invention is particularly directed to the use of oneor more diterpenes from a member of the Euphorbiaceae family of plantsor botanical or horticultural relatives of such plants. Reference hereinto a member of the Euphorbiaceae family includes reference to speciesfrom the genera Acalypha, Acidoton, Actinostemon, Adelia, Adenocline,Adenocrepis, Adenophaedra, Adisca, Agrostistachys, Alchornea,Alchorneopsis, Alcinaeanthus, Alcoceria, Aleurites, Amanoa, Andrachne,Angostyles, Anisophllum, Antidesmia, Aphora, Aporosa, Aporosella,Argythamnia, Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia,Beyeriopsis, Bischofia, Blachia, Blumeodondron, Bonania, Bradleia,Breynia, Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron,Celianella, Cephalocroton, Chaenotheca, Chaetocarpus, Chanaesyce,Cheilosa, Chiropetalum, Choriophyllum, Cicca, Chaoxylon, Cleidon,Cleistanthus, Cluytia, Cnesmone, Cnidoscolus, Coccoceras, Codiaeum,Coelodiscus, Conami, Conceveiba, Conceveibastrum, Conceveibum, Corythea,Croizatia, Croton, Crotonopsis, Crozophora, Cubanthus, Cunuria,Dactylostemon, Dalechampia, Dendrocousinsia, Diaspersus, Didymocistus,Dimorphocalyx, Discocarpus, Ditaxis, Dodecastingma, Drypetes, Dysopsis,Elateriospermum, Endadenium, Endospermum, Erismanthus, Erythrocarpus,Erythrochilus, Eumecanthus, Euphorbia, Euphorbiodendron, Excoecaria,Flueggea, Calearia, Garcia, Gavarretia, Gelonium, Giara, Givotia,Glochidion, Clochidionopsis, Glycydendron, Gymnanthes, Gymnosparia,Haematospermum, Hendecandra, Hevea, Hieronima, Hieronyma,Hippocrepandra, Homalanthus, Hymenocardia, Janipha, Jatropha,Julocroton, Lasiocroton, Leiocarpus, Leonardia, Lepidanthus,Leucocroton, Mabea, Macaranga, Mallotus, Manihot, Mappa, Maprounea,Melanthesa, Mercurialis, Mettenia, Micrandra, Microdesmis, Microelus,Microstachy, Maocroton, Monadenium, Mozinnia, Neoscortechinia,Omalanthus, Omphalea, Ophellantha, Orbicularia, Ostodes, Oxydectes,Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilandthus, Pera,Peridium, Petalostigima, Phyllanthus, Picrodendro, Pierardia,Pilinophytum, Pimeleodendron, Piranhea, Platygyna, Plukenetia,Podocalyx,, Poinsettia, Poraresia, Prosartema, Pseudanthus, Pycnocoma,Ouadrasia, Reverchonia, Richeria, Richeriella, Ricinella, Ricinocarpus,Rottlera, Sagotia, Sanwithia, Sapium, Savia, Sclerocroton, Sebastiana,Securinega, Senefeldera, Senefilderopsis, Serophyton, Siphonia,Spathiostemon, Spixia, Stillingia, Strophioblachia, Synadenium,Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanthera, Tithymalus,Trageia, Trewia, Trigonostemon, Tyria and Xylophylla.

[0036] The most preferred genus and most suitable for the practice ofthe present invention is the genus Euphorbia. Particularly usefulspecies of this genus include Euphorbia aaron-rossii, Euphorbiaabbreviata, Euphorbia acuta, Euphorbia alatocaulis, Euphorbiaalbicaulis, Euphorbia algomarginata, Euphorbia aliceae, Euphorbia alta,Euphorbia anacampseros, Euphorbia andromedae, Euphorbia angusta,Euphorbia anthonyi, Euphorbia antiguensis, Euphorbia apocynifolia,Euphorbia arabica, Euphorbia ariensis, Euphorbia arizonica, Euphorbiaarkansana, Euphorbia arteagae, Euphorbia arundelana, Euphorbiaastroites, Euphorbia atrococca, Euphorbia baselicis, Euphorbiabatabanensis, Euphorbia bergeri, Euphorbia bermudiana, Euphorbiabicolor, Euphorbia biformis, Euphorbia bifurcata, Euphorbia bilobata,Euphorbia biramensis, Euphorbia biuncialis, Euphorbia blepharostipula,Euphorbia blodgetti, Euphorbia boerhaavioides, Euphorbia boliviana,Euphorbia bracei, Euphorbia brachiata, Euphorbia brachycera, Euphorbiabrandegee, Euphorbia brittonii, Euphorbia caesia, Euphorbia calcicola,Euphorbia campestris, Euphorbia candelabrum, Euphorbia capitellata,Euphorbia carmenensis, Euphorbia carunculata, Euphorbia cayensis,Euphorbia celastroides, Euphorbia chalicophila, Euphorbia chamaerrhodos,Euphorbia chamaesula, Euphorbia chiapensis, Euphorbia chiogenoides,Euphorbia cinerascens, Euphorbia clarionensis, Euphorbia colimae,Euphorbia colorata, Euphorbia communtata, Euphorbia consoquitlae,Euphorbia convolvuloides, Euphorbia corallifera, Euphorbia creberrima,Euphorbia crenulata, Euphorbia cubensis, Euphorbia cuspidata, Euphorbiacymbiformis, Euphorbia darlingtonii, Euphorbia defoliata, Euphorbiadegeneri, Euphorbia deltoidea, Euphorbia dentata, Euphorbia depressaEuphorbia dictyosperma, Euphorbia dictyosperma, Euphorbia dioeca,Euphorbia discoidalis, Euphorbia dorsiventralis, Euphorbia drumondii,Euphorbia duclouxii, Euphorbia dussii, Euphorbia eanophylla, Euphorbiaeggersii, Euphorbia eglandulosa, Euphorbia elata, Euphorbia enzalla,Euphorbia eriogonoides, Euphorbia eriophylla, Euphorbia esculaeformis,Euphorbia espirituenisis, Euphorbia esula, Euphorbia excisa, Euphorbiaexclusa, Euphorbia exstipitata, Euphorbia exstipulata, Euphorbiafendleri, Euphorbia filicaulis, Euphorbia filiformis, Euphorbia florida,Euphorbia fruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbiagerardiania, Euphorbia geyeri, Euphorbia glyptosperma, Euphorbiagorgonis, Euphorbia gracilior, Euphorbia gracillima, Euphorbia gradyi,Euphorbia graminea, Euphorbia graminiea Euphorbia grisea, Euphorbiaguadalajarana, Euphorbia guanarensis, Euphorbia gymnadenia, Euphorbiahaematantha, Euphorbia hedyotoides, Euphorbia heldrichii, Euphorbiahelenae, Euphorbia helleri, Euphorbia helwigii, Euphorbia henricksonii,Euphorbia heterophylla, Euphorbia hexagona, Euphorbia hexagonoides,Euphorbia hinkleyorum, Euphorbia hintonii, Euphorbia hirtula, Euphorbiahirta, Euphorbia hooveri, Euphorbia humistrata, Euphorbia hypericifolia,Euphorbia inundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbiajejuna, Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii,Euphorbia lasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbialatericolor, Euphorbia laxiflora Euphorbia lecheoides, Euphorbialedienii, Euphorbia leucophylla, Euphorbia lineata, Euphorbialinguiformis, Euphorbia longecornuta, Euphorbia longepetiolata,Euphorbia longeramosa, Euphorbia longinsulicola, Euphorbia longipila,Euphorbia lupulina, Euphorbia lurida, Euphorbia lycioides, Euphorbiamacropodoides, macvaughiana, Euphorbia manca, Euphorbia mandoniania,Euphorbia mangleti, Euphorbia mango, Euphorbia marylandica, Euphorbiamayana, Euphorbia melanadenia, Euphorbia melanocarpa, Euphorbiameridensis, Euphorbia mertonii, Euphorbia mexiae, Euphorbiamicrocephala, Euphorbia microclada, Euphorbia micromera, Euphorbiamisella, Euphorbia missurica, Euphorbia montana, Euphorbia montereyana,Euphorbia multicaulis, Euphorbia multiformis, Euphorbia multinodis,Euphorbia multiseta, Euphorbia muscicola, Euphorbia neomexicana,Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia oaxacana,Euphorbia occidentalis, Euphorbia odontodemia, Euphorbia olivacea,Euphorbia olowaluana, Euphorbia opthalmica, Euphorbia ovata, Euphorbiapachypoda, Euphorbia pachyrhiza, Euphorbia padifolia, Euphorbia palmeri,Euphorbia paludicola, Euphorbia paralias, Euphorbia parciflora,Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana, Euphorbiapediculifera, Euphorbia peplidion, Euphorbia peploides, Euphorbiapeplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbia petaloidea,Euphorbia petaloidea, Euphorbia petrina, Euphorbia picachensis,Euphorbia pilosula, Euphorbia pilulifera, Euphorbia pinariona, Euphorbiapinetorum, Euphorbia pioniosperma, Euphorbia platysperma, Euphorbiaplicata, Euphorbia poeppigii, Euphorbia poliosperma, Euphorbiapolycarpa, Euphorbia polycnemioides, Euphorbia polyphylla, Euphorbiaportoricensis, Euphorbia portulacoides Euphorbia portulana, Euphorbiapreslii, Euphorbia prostrata, Euphorbia pteroneura, Euphorbiapycnanthema, Euphorbia ramosa, Euphorbia rapulum, Euphorbia remyi,Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis,Euphorbia robusta, Euphorbia romosa, Euphorbia rubida, Euphorbiarubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbiasaxatilis M. Bieb, Euphorbia schizoloba, Euphorbia sclerocyathium,Euphorbia scopulorum, Euphorbia senilis, Euphorbia serpyllifolia,Euphorbia serrula, Euphorbia setiloba Engelm, Euphorbia sonorae,Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerosperma,Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea,Euphorbia stellata, Euphorbia submammilaris, Euphorbia subpeltata,Euphorbia subpubens, Euphorbia subrenforme, Euphorbia subtrifoliata,Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides,Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli,Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii,Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor,Euphorbia troyana, Euphorbia tuerckheimii, Euphorbia turczaninowii,Euphorbia umbellulata, Euphorbia undulata, Euphorbia vermiformis,Euphorbia versicolor, Euphorbia villifera, Euphorbia violacea, Euphorbiawhitei, Euphorbia xanti Engelm, Euphorbia xylopoda Greenm., Euphorbiayayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica andEuphorbia zinniiflora.

[0037] Particularly preferred species of the genus Synadenzium includeSynadenium grantii and Synadenium compactum.

[0038] Particularly preferred species of the genus Monadenium includeMonadenium lugardae and Monadenium guentheri.

[0039] A preferred species of the genus Endadenium is Endadeniumgossweileni.

[0040]Euphorbia peplus is particularly useful and is preferred in thepractice of the present invention. Reference herein to “Euphorbiapeplus” or its abbreviation “E. peplus” includes various varieties,strains, lines, hybrids or derivatives of this plant as well as itsbotanical or horticultural relatives. Furthermore, the present inventionmay be practiced using a whole Euphorbiaceae plant or parts thereofincluding sap or seeds or other reproductive material may be used.Generally, for seeds or reproductive material to be used, a plant orplantlet is first required to be propagated.

[0041] Reference herein to a Euphorbiaceae plant, a Euphorbia species orE. peplus further encompasses genetically modified plants. Geneticallymodified plants include transgenic plants or plants in which a trait hasbeen removed or where an endogenous gene sequence has beendown-regulated, up-regulated, mutated or otherwise altered including thealteration or introduction of genetic material which exhibits aregulatory effect on a particular gene. Consequently, a plant whichexhibits a character not naturally present in a Euphorbiaceae plant or aspecies of Euphorbia or in E. peplus is nevertheless encompassed by thepresent invention and is included within the scope of theabove-mentioned terms. Furthemiore, the present invention contemplateshybrid plant cells or plants comprising hybrid plant cells formed by thefusion of two or more plant cells from different strains, species orgenera and optionally regenerating a plant therefrom. Such hybrid plantcells are proposed to generate novel secondary metabolites having usefultherapeutic properties.

[0042] The diterpenes are generally in extracts of the Euphorbiaceaeplants. An extract may comprise, therefore, sap or liquid or semi-liquidmaterial exuded from, or present in, leaves, stem, flowers, seeds andbark or between the bark and the stem. Most preferably, the extract isfrom sap. Furthermore, the extract may comprise liquid or semi-liquidmaterial located in fractions extracted from sap, leaves, stems,flowers, bark or other plant material of the Euphorbiaceae plant. Forexample, plant material may be subject to physical manipulation todisrupt plant fibres and extracellular matrix material and inter- andintra-tissue extracted into a solvent including an aqueous environment.The fractions may include aqueous or alcohol extracts. Other extractionmedia are also contemplated including fractions prepared by HPLC orother fractionation systems. All such sources of the diterpenes areencompassed by the present invention including diterpenes obtained bysynthetic routes.

[0043] The preferred diterpenes are selected from compounds of theingenane, pepluane and jatrophane families. A compound is stated to be amember of the ingenane, pepluane or jatrophane families on the basis ofchemical structure and/or chemical or physical properties. A compoundwhich is a derivative of an ingenane, pepluane or jatrophane isnevertheless encompassed by the present invention through use of theterms “ingenane”, “pepluane” or “jatrophane” since these tenus includederivatives, chemical analogs and chemically synthetic forms of thesefamilies of compounds. One particularly preferred derivative is anangeloyl-substituted derivative of ingenane.

[0044] The chemical agents of the present invention may be in purifiedor isolated form meaning that the preparation is substantially devoid ofother compounds or contaminating agents other than diluent, solvent orcarrier or isoforms of the agents. Furthermore, the term “chemicalagent” includes preparations of two or more compounds either admixedtogether or co-purified from a particular source. The. chemical agentmay also be a chemical fraction, extract or other preparation includingsap from the Euphorbiaceae plant. The chemical agents or extracts orfractions of the present invention may also be referred to as “drugs” or“actives” or “active ingredients”. The term “agent” is not to imply asynthetic compound and may include a fraction obtainable from the sap ofthe Euphorbiaceae plant. The term “obtainable” also includes “obtained”.

[0045] Consequently, reference herein to a “chemical agent” includes apurified form of one or more compounds or a chemical fraction or extractsuch as from the sap of a Euphorbiaceae plant, and in particular aspecies of Euphorbia, and most preferably from E. peplus or botanical orhorticultural relatives or variants thereof.

[0046] Accordingly, one aspect of the present invention contemplates amethod for the treatment or prophylaxis of prostate cancer or a relatedcancer or condition, said method comprising the administration to saidsubject of a symptom-ameliorating effective amount of a chemical agentobtainable from a plant of the Euphorbiaceae. family or a derivative orchemical analog thereof which chemical agent is a diterpene selectedfrom compounds of the ingenane, pepluane and jatrophane families andwhich chemical agent or derivative or chemical analog is represented byany one of the general formulae (I)-(V)

[0047] wherein:

[0048] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphors, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0049] A-T are independently selected fiom hydrogen, R₁, R₂, R₃, F, Cl,Br, I, CN, OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁,SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂,(C=X)R₃ or X(C=X)R₃ where X is selected from sulfur, oxygen andnitrogen;

[0050] R₁ and R₂ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ allcoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁, SR₁,NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂,SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂]alkyl;

[0051] R₃ is selected from R₁, R₂, CN, COR₁, CO₂R₁, OR₁, SR₁, NR₁R₂,N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂,P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂;

[0052] A connected to B (or C), D (or E), R (or Q), P (or O) or S (or T)is a selection of C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic rings further substituted by R₃, (C=X)R₃ andX(C=X)R₃, including epoxides and thioepoxides;

[0053] J connected to I (or H), G (or F), K (or L), M (or N) or S (or T)is a selection of C₁-C₈ disubstituted (fused) saturated and unsaturatedcarbocyclic or heterocyclic rings further substituted by R₃, (C=X)R₃ andX(C=X)R₃, including epoxides and thioepoxides;

[0054] D (or E) connected to B (or C) or G (or F); I (or H) connected toG (or F); P (or O) connected to R (or Q) or M (or N); K (or L) connectedto N (or M) is a selection of C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic rings substituted by R₃, (C=X)R₃and X(C=X)R₃, including epoxides and thioepoxides;

[0055] B and C, D and E, R and Q, P and O, I and H, G and F, K and L Mand N or S and T are =X where X is selected from sulfur, oxygen,nitrogen, NR₁R₂, and =CriR₂

[0056] wherein:

[0057] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0058] A′-T′ are independently selected from hydrogen, R₄, R₅, R₆, F,Cl, Br, I, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅, CONR₄R₅, N(=O)₂, NR₄OR₅,ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃,P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂, (C=X)R₆ or X(C=X)R₆ where X is selectedfrom sulfur, oxygen and nitrogen;

[0059] R₄ and R₅ are each, independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₄, SR₄,NR₄R₅, N(=O)₂, NR₄RO₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅,SO₃NR₄R₅, P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂]alkyl;

[0060] R₆ is selected from R₄, R₅, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅,N(=O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₅,P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂;

[0061] E′ and R′ or H′ and O′ is a C₂-C₈ saturated or unsaturatedcarbocyclic or heterocyclic ring system further substituted by R₆,including epoxides and thioepoxides;

[0062] O′ connected to M′ (or N′) or Q′ (or P′); R′ connected to Q′60(or P′) or S′ (or T′); S′ (or T′) connected to A′ (or B′); A′ (or B′)connected to C′ (or D′); E′ connected to C′ (or D′) or F′ (or G′); H′connected to I′; I′ connected to J′; J′ connected to K′; K′ connected toL′; L′ connected to M′ (or N′) are C₁-C₈ disubstituted (fused) saturatedor unsaturated carbocyclic or heterocyclic ring systems furthersubstituted by R₆, (C=X)R₆ and X(C=X)R₆, including epoxides andthioepoxides;

[0063] A′, B′and C′, D′and F′, G′and M′, N′and P′Q′and S′T′are =X whereX is selected from sulfur, oxygen, nitrogen, NR4R₅, (C=X)R₆, X(CX)R₆,and =CR₇R₈; R₇ and R₈ are each independently selected from R₆, (C=X)R₆and X(C=X)R₆

[0064] wherein:

[0065] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0066] A¹-T¹ are independently selected from hydrogen, R₉, R₁₀, R₁₁, F,Cl, Br, I, CN, OR₉, SR₉, NR₉R₁₀, N(=O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉,SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃,B(R₉)₂, (C=X)R₁₁ or X(C=X)R₁₁, where X is selected from sulfiur, oxygenand nitrogen;

[0067] R₉ and R₁₀ are each independently selected from C₁-C₂₀ alkyl(branched and straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-CI₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and straight chained), C₂-C₁₀ alkynyl (branched and straightchained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl,dihaloalkyl, trialoalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₉, SR₉, NR₉R₁₀,N(=O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀,SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂]alkyl;

[0068] R₁₁, is selected from R₉, R₁₀, CN, COR₉, CO₂R₉, OR₉, SR₉, NR₉R₁₀,N(=O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀,SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂;

[0069] B¹ and R¹, E¹ and Ö¹ and Ë¹ and M¹ are selected from a C₂-C₈saturated or unsaturated carbocyclic or heterocyclic ring system furthersubstituted by R₁₁, including epoxides and thioepoxides;

[0070] A¹ (or Ä¹ connected to Á¹ (or Ã¹) or T¹ (or S¹); B¹ connected toÁ¹ (or Ã¹) or C¹ (or D¹). E¹ connected to Ë¹ or C¹ (or D¹); Ë¹ connectedto É¹ (or F¹); G¹ (or H¹) connected to É¹ (or F¹) or I¹ (or J¹); K¹ (orL¹) connected to I¹ (or J¹) or M¹; M¹ connected to O¹ (or N¹); Ö¹connected O¹ (or N¹) or P¹ (or Q¹); R¹ connected P¹ (or Q¹) or S¹ (orT¹) are C₁-C₈ disubstituted (fused) saturated or unsaturated carbocyclicor heterocyclic ring systems further substituted by R₁₁, (C=X)R₁₁, andX(C=X)R₁₁, including epoxides and thioepoxides;

[0071] A¹, Ä and Á, Ã and C¹, D¹ and F¹, É and G¹, H¹ and I¹, J¹ and K¹,L¹ and N¹, O¹ and P¹, Q¹ and S¹, T¹ are =X where X is selected fromsulfur, oxygen, nitrogen, NR₉R₁₀, including (C=X)R₁₁, and X(C=X)R₁₁, and=CR₁₂R₁₃;

[0072] R₁₂ and R₁₃ are independently selected from R₁₁, (C=X)R₁₁, andX(C=X)R₁₁,

[0073] wherein:

[0074] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0075] A²-X² are independently selected from hydrogen, R₁₄, R₁₅, R₁₆, F,Cl, Br, I, CN, OR₁₄, SR₁₄, NR₁₄R₁₅, N(=O)₂, NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄,SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅, P(R₁₄)₃, P(=O)(R₁₄)₃,Si(R₁₄)₃, B(R₁₄), (C=Y)R₁₆ or Y(C=Y)R₁₆ where Y is selected from sulfur,oxygen and nitrogen;

[0076] R₁₄ and R₁₅ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ allkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₄,SR₁₄, NR₁₄R₁₀ , N(=O)₂, NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄,SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅, P(R₁₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃,B(R₁₄)₂]alkyl;

[0077] R₁₆ is selected from R₁₄, R₁₅, CN, COR₁₄, CO₂R₁₅, OR₁₄, SR₁₄,N₁₄R₁₅, N(=O)₂, NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, S₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅,SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅, P(R₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂;

[0078] E² and V², and H² and S², and I² and P² are C₂-C₈ saturated orunsaturated carbocyclic or heterocyclic ring system further substitutedby R₁₆, including epoxides and thioepoxides;

[0079] A² (or B²) connected to C² (or D²) or W² (or X²); E² connected toC² (or D²) or F² (or G²); H² connected to F² (or G² or I²; I² connectedto J² (or K²); L² (or M²) connected to J² (or K²) or N² (or O²); R² (orQ² connected to P² or S²; V² connected to U² (or T²) or W² (or X²) areC₁-C₈ disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic ring systems further substituted by R₁₆, (C=Y)R₁₆ andY(C=Y)R₁₆, including epoxides and thioepoxides;

[0080] A², B²; C², D²; F², G²; J², K²; L², M²; N², O²; O², R²; U², T²and X², W² are =Y where Y is selected from sulfur, oxygen, nitrogen,NR₁₄R₁₅ and =CR₁₇R₁₈;

[0081] R₁₇ and R₁₈ are independently selected from R₁₆, (C=Y)R₁₆ andY(C=Y)R₁₆

[0082] wherein:

[0083] n is 0-10 atoms selected from carbon, oxygen, nitrogen, suilfr,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0084] A³-Z³ are independently selected from hydrogen, R₁₉, R₂₀, R₂₁, F,Cl, Br, I, CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉,SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃, P(=O)(R₁₉)₃,Si(R₁₉)₃, B(R₁₉)₂, (C=Ø)R₂₁ or Ø (C=Ø)R₂₁ where Ø is sulfur, oxygen andnitrogen;

[0085] R₁₉ and R₂₀ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ allkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₉,SR₁₉, NR₁₉R₂₀, N(=O)₂, NR,₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉,SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃,B(R₁₉)₂]alkyl;

[0086] R₂₁ is selected from R₁₉, R₂₀, CN, COR₁₉, CO₂R₁₉, OR₁₉, SR₁₉,NR₁₉R₂₀, N(=O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀,SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂;

[0087] D³ connected to X³ is a C₂-C₈ saturated or unsaturatedcarbocyclic or heterocyclic ring system further substituted by R₂₁,including epoxides and thioepoxides; A³ (or Ä³) connected to B³ (or C³)or Z³ (or Y³); D³ connected to B³ (or C³) or E³ (or F³); G³ (or H³)connected to E³ (or F³) or I³ (or J³); L³ (or K³) connected to I³ (orJ³) or M³ (or N³); O³ (or Ö³) connected to N³ (or M³) or P³ (or Q³). S³(or R³) connected to Q³ (or P³) or U³ (or T³). W³ (or V³) connected toU³ (or T³) or X³; X³ connected to Y³ (or Z³) are C₁-C₈ disubstituted(fused) saturated or unsaturated carbocyclic or heterocyclic ringsystems further substituted by R₂₁, (C=Ø)R₂₁ and Ø (C=Ø)R₂₁, includingepoxides and thioepoxides;

[0088] A³, A³;B³,C³; E³,F³; G³, H³; I³, J³; K³, L³; M³,N³; O³, {umlautover (0)}³; Q³,P³, R³, U³, T³, W³, V³, and Z³,Y³ are =Ø where Ø isselected from sulfur, oxygen, nitrogen, NR₁₉R₂₀, and =CR₂₂R₂₃; and

[0089] R₂₂ and R₂₃ are selected from R₂₁, (C=Ø)R₂₁ and Ø (C=Ø)R₂₁;

[0090] wherein said chemical agent or its derivatives or chemicalanalogs is administered for a time and under conditions sufficient. toameliorate one or more symptoms associated with said prostate cancer ora related condition.

[0091] More particularly, the present invention is directed to a methodfor the treatment or prophylaxis of prostate cancer or a relatedcondition in an subject, said method comprising the administration tosaid subject of a symptom-ameliorating effective amount of a chemicalagent obtainable from E. peplus or a derivative or chemical analogthereof which chemical agent is a diterpene selected from compounds ofthe ingenane, pepluane and jatrophane families and which chemical agentor derivative or chemical analog is represented by any one of thegeneral formulae (I)-(V) as defined herein and wherein said chemicalagent or its derivatives or chemical analogs is administered for a timeand under conditions sufficient to ameliorate one or more symptomsassociated with said prostate cancer.

[0092] In a related embodiment, the subject chemical agents may be usedto increase the sensitivity of prostate cancer cells to the activity ofthe immune system or to chemical agents or otherwise be used topotentiate the immune system against prostate cancer cells. This methodinvolves the administration to a subject of the chemical agents of theinvention. In an alternative embodiment, the prostate cancer cells maybe removed such as by biopsy, treated with the subject chemical agentsand returned to the subject in order to induce a more potent immuneresponse against the prostate cancer cells.

[0093] Accordingly, the present invention provides a method forimmunopotentiation of a subject in the treatment and prophylaxis of saidsubject for prostate cancer or a related cancer or condition, saidmethod comprising administration to said subject of asymptom-ameliorating effective amount of a diterpene, or a chemicalfraction comprising same from a plant of the Euphorbiaceae or aderivative or chemical analog of said diterpene having the structures asdefined herein, said administration being for a time and underconditions sufficient to potentiate components of the immune systemagainst prostate cancer cells.

[0094] Especially preferred chemical agents or derivatives or chemicalanalogs thereof in the practice of the present invention are representedby the general formula (VI):

[0095] wherein:

[0096] R₂₄, R₂₅ and R₂₆ are independently selected from hydrogen, R₂₇,R₂₈, F, Cl, Br, I, CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, Nr₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(=O)(R₂₇)₃,Si(R₂₇)₃, B(R₂₇)₂, (C=X)R₂₉ or X(C=X)R₂₉ where X is selectedfrom sulfur, oxygen and nitrogen;

[0097] R₂₇ and R₂₈ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C14 heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₂₇,SR₂₇, NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇,SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃, P(O)(R₂₇)₃, Si(R₂₇)₃,B(R₂₇)₂]alkyl;

[0098] R₂₉ is selected from R₂₇, R₂₈, CN, COR₂₇, CO₂R₂₇, OR₂₇, SR₂₇,NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈,SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃, P(=O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂.

[0099] In a preferred embodiment, R₂₄ is hydrogen, OAcetyl or OH.

[0100] In another preferred embodiment, R₂₅ is OH.

[0101] In another preferred embodiment, R₂₆ is OH.

[0102] As used herein, the term “alkyl” refers to linear or branchedchains. The term “haloalkyl” refers to an alkyl group substituted by atleast one halogen. Similarly, the term “haloalkoxy” refers to an alkoxygroup substituted by at least one halogen. As used herein the term“halogen” refers to fluorine, chlorine, bromine and iodine.

[0103] As used herein the term “aryl” refers to aromatic carbocyclicring systems such as phenyl or naphthyl, anthracenyl, especially phenyl.Suitably, aryl is C₆-C₁₄ with mono, di- and tri-substitution containingF, Cl, Br, I, NO₂, CF₃, CN, OR₁, COR₁, CO₂R₁, NHR₁, NR₁R₂, NR₁₀R₂,ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃,P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂, wherein R₁ and R₂ are defined above

[0104] As used herein the terms “heterocycle”, “heterocyclic”,“heterocyclic systems” and the like refer to a saturated, unsaturated,or aromatic carbocyclic group having a single ring, multiple fused rings(for example, bicyclic, tricyclic, or other similar bridged ring systemsor substituents), or multiple condensed rings, and having at least oneheteroatom such as nitrogen, oxygen, or sulfur within at least one ofthe rings. This term also includes “heteroaryl” which refers to aheterocycle in which at least one ring is aromatic. Any heterocyclic orheteroaryl group can be unsubstituted or optionally substituted with oneor more groups, as defined above. Further, bi- or tricyclic heteroarylmoieties may comprise at least one ring, which is either completely, orpartially, saturated. Suitable heteroaryl moieties include, but are notlimited to oxazolyl, thiazaoyl, thienyl, furyl, 1-isobenzofuranyl,3H-pyrrolyl, 2H-pyrrolyl, N-pyrrolyl, imidazolyl, pyrazolyl,isothiazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyradazinyl,indolizinyl, isoindolyl, indoyl, indolyl, purinyl, phthalazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazoyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl,1,2,3,5-oxatriazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,azepinyl, oxepinyl, thiepinyl, benzofuranyl, isobenzofuranyl,thionaphthenyl, isothionaphthenyl, indoleninyl, 2-isobenzazolyl,1,5-pyrindiiiyl, pyrano[3,4-b]pyrrolyl, isoindazolyl, indoxazinyl,benzoxazolyl, anthranilyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, naphtliyridinyl, pyrido[3,4-b]pyridinyl, andpyrido[3,2-b]pyridinyl, pyrido[4,3-b]pyridinyl.

[0105] Particularly useful compounds in accordance with the presentinvention include 5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane), derivatives of said pepluane, jatrophanesof Conformation II including2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17), 11E-diene(jatrophane 1), derivatives of said jatrophane 1,2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy- 15-hydroxy-jatropha-6(17),11E-diene (jatrophane 2), derivatives of said jatrophane 2,2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxy-jatropha-6(17),11E-diene jatrophane 3), derivatives of said jatrophane 3,2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxyjatropha-6(17),11E-diene) jatrophane 4), derivatives of said jatrophane 4, 2,5,7,14-tetraacetoxy-3-benzoyloxy-8, 15-dihydroxy-9-nicotinoyloxyjatropha-6(17), 11E-diene (jatrophane 5), derivatives of said jatrophane5,2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),11E-dienejatrophane 6), derivatives of said jatrophane 6, or pharmaceuticallyacceptable salts of these.

[0106] Even more particularly preferred compounds are angeloylsubstituted ingenanes or derivatives thereof such as ingenol-3-angelate,20-deoxy-ingenol-3-angelate, 20-O-acetyl-ingenol-3-angelate, orderivatives of said angelates, or pharmaceutically acceptable salts ofthese.

[0107] The present invention extends to all functional jatrophane orpepluane derivatives. For example, such derivatives include acetylderivatives (e.g. jatrophane 4 with an acetylation of the 8-hydroxylgroup), deacytlated derivatives (e.g. jatrophane 1 with a deacetylationof the 2-hydroxy group). Pepluane derivatives as described by Hohmann etal. (1999) or with a hydroxylation of the 10-hydroxy group and all ofthe compounds described in Inteniational Patent Application No.PCT/AU98/00656, International Patent Application No. PCT/AU01/00678,International Patent Application No. PCT/AU01/00679 and InternationalPatent Application No. PCT/AU01/00680 are also within the scope of thepresent invention. Other exemplary derivatives contemplated by thepresent invention include angeloyl derivatives of jatrophanes andpepluanes, tiglic acid derivatives and derivatives comprising thetrans-isomer of angelic acid. Derivatives or analogs of the compoundsalso include alterations which change the hydrophilicity orhydrophobicity of the molecule so as to improve its transport in abiological system are also encompassed within this scope. Suitablemodifications can readily be effected and tested using methods known inthe art. Whilst not intending to limit the invention to any proposedmechanism or action, it is proposed that activation can lead todown-regulation of protein kinase C (PKC) via the rapid destruction ofactivated enzyme and thus the beneficial effect may be due to theultimate down-regulation of PKC activity or of PKC-mediated signallingin addition to direct killing of prostate cancer cells. Furthennore,again not wishing to limit the present invention to any one theory ormode of action, it is possible that a sum or all of the chemical agentsof the invention mediate effects against cancer cells via activation ofinflammatory cells and/or by the induction of cytokines and/orchemokines.

[0108] Accordingly, a particularly preferred embodiment of the presentinvention contemplates a method for the treatment or prophylaxis of asubject with prostate cancer or a related cancer or condition or withthe symptoms of prostate cancer, said method comprising theadministration to said subject of a symptom-ameliorating effectiveamount of an angeloyl- substituted ingenane or a chemical fiaction orplant extract comprising same.

[0109] Even more preferably, the present invention provides a method forthe treatment or prophylaxis of a subject with prostate cancer or arelated cancer or condition or with the symptoms of prostate cancer,said method comprising the administration to said subject of asymptom-ameliorating effective amount of one or more ofingenol-3-angelate, 20-deoxy-ingenol-3-angelate and/or20-O-acetyl-ingenol-3-angelate or a derivative thereof or apharmaceutically acceptable salt of these or a chemical fraction orplant extract comprising same. Preferably, the derivative is selectedfiom an ester derivative or an acetylated derivative.

[0110] The chemical agents of the present invention may be alsooptionally coupled to a targeting agent. This may suitably be abone-seeking agent such as a bisphosphonate, in order to target thechemical agents to bone metastases or an antibody directed to aprostate-specific tumor marker such as prostate-specific antigen (PSA),prostate-specific membrane antigen (PSMA), PSA receptor or otherprostate cancer antigen, in order to target the active compound toprostate cancer cells. A preferred bisphosphonate is methylenedisphosphonate. Where an antibody is used, the antibody is preferablymonoclonal and more preferably is a humanized or human monoclonalantibody. Antibodies may be specific not only to prostate-specific tumormarkers but also to components of the immune system such as dendriticcells, B- or T-cells. Methods for making such monoclonal antibodies andsuitable methods for coupling the active agent to the targeting agentare well known in the art.

[0111] Representative coupling methods for linking the chemical agentsof the invention through covalent or non-covalent bonds to the targetingagent include chemical cross-linkers and heterobifunctionalcross-linking compounds (i.e. “linkers”) that react to form a bondbetween reactive groups (such as hydroxyl, amino, amido, or sulfhydrylgroups) in a chemnical agent and other reactive groups (of a similarnature) in the targeting agent. This bond may be, for example, a peptidebond, disulfide bond, thioester bond, amiide bond, thioether bond andthe like. In one illustrative example, conjugates of monoclonalantibodies with drugs have been summarized by Morgan and Foon(Monoclonal Antibody Therapy to Cancer: Preclinical Models andInvestigations, Basic and Clinical Tumor Immunology, Vol. 2, KluwerAcademic Publishers, Hingham, Mass.) and by Uhr J. of Immunol.133:i-vii, 1984). In another illustrative example where the conjugatecontains a radionuclide cytostatic agent, U.S. Pat. No. 4,897,255(Fritzberg et al.) is instructive of coupling methods that may beuseful. In a preferred embodiment, the therapeutic conjugate contains ametastasis- or prostate cancer specific antigen-binding protein (e.g.monoclonal antibody) coupled covalently to a chemical agent of theinvention. In this case, the covalent bond of the linkage may be formedbetween one or more amino, sulfhydryl, or carboxyl groups of the bindingprotein and (a) the chemical agent itself; (b) a carboxylic acid of thechemical agent; (c) an ester of the chemical agent; or (d) complexes ofthe chemical agent with poly-L-lysine or any polymeric carrier.

[0112] The choice of coupling method will be influenced by the choice oftargeting agent and the chemical agent and also by such physicalproperties as, e.g. shelf life stability and/or by such biologicalproperties as, e.g. half-life in cells and blood, intracellularcompartmentalisation route and the like.

[0113] Reference herein to a subject includes a human, primate,livestock animal (e.g. sheep, cow, horse, pig, goat, donkey), laboratorytest animal (e.g. mouse, rat, guinea pig, hamster) or companion animal(e.g. dog, cat). The above-mentioned animals may also be useful inanimal models for prostate cancer and the use of the subject chemincalagents in an animal model is considered useful in accordance with thepresent invention.

[0114] The preferred subject is a human or primate or laboratory testanimal.

[0115] The most preferred subject is a human.

[0116] The present invention further contemplates the use of the subjectchemical agents in combination with other therapeutic procedures used inthe treatment of prostate cancer and/or in the amelioration of symptomsassociated with prostate cancer.

[0117] Accordingly, another aspect of the present invention contemplatesa method for -the treatment or prophylaxis of prostate cancer or arelated cancer or condition in a subject, said method comprising thesimultaneous or sequential administration to said subject of asymptom-ameliorating effective amount of a chemical agent derived from aplant of the Euphorbiaceae family as hereinbefore described togetherwith a therapeutic protocol or a symptom-ameliorating effective amountof another chemical agent or a physical agent.

[0118] For example, the subject chemical agents from Euphorbiaceae maybeused simultaneously with or sequentially to or otherwise in combinationwith chemotherapeutic agents. Such agents include the compoundsgemicitabine, herceptin, irinotecan, leustatin navelbine, rituxan, STI571, taxotere, topotecan, xeloda, zometa vinblastinie, vinorelbine,vinaesine, treosulfan, tomudex, thiotepa, thioquaunine, streptozocin,procabazine, intomycin, methotrexate mercaptopuiine, melphaan,lomustine, irinotecan, ipospainide, idarubicin, gemcitabine fludarabine,etoposide, epiiubicin, doxorubicin, paunorubicin, dacarbazine,cytarabine, cyclophosphamide, cisplatin, chlorambucil, carmnustine,carboplatin, busulphan, bleomycin, asparaginase, adriamycin,actinonmycin P, lmitoxantbrone, prednisone, taxol VP-16 andketokonazole.

[0119] The present invention also provides for use of chenmopreventiveagents in combination with the chemical agents of the invention. Suchchemopreventive agents include toremifene analogs or metabolites thereofwhich are well Icnown to those skilled in the art. Other examples ofcancer chemopreventive agents include4-chlioro-1,2-diphenyl-1-[4-[2-(N-methylamino) ethoxy]phenyl] -1-butene;4-chloro-1,2-diphenyl-4-[4-[2-(N,N-1 -diethyl-(amino)ethoxy]phenyl]-1-butene; 4-chloro-1,2-diphenyl-1-14-(aminoethoxy)phenyl]- 1-butene; 4-chloro-1-(4-hydroxyphenyl)-1-[4-[2-(N,N-dimethylamnino)ethoxy]phenyl]-2-phenyl-1-butene;4-chloro--(4-hydroxyphenyl)-1-[4-[2-(N-methylanino)ethoxy]phenyl]-2-phenyl-1-butene;and 4-chloro-1,2-bis(4-hydroxyphenyl)-1-[4-[2-(N,N-dimethyl-amino)ethoxy]phenyl]-1-butene.

[0120] “Sequential” treatment includes the administration ofEuphorbiaceae compounds and the chemotherapeutic compounds in eitherorder and within seconds, minutes, hours, days, weeks for months.“Simultaneous” treatment means the agents are administeredsubstauntially at the same time such as in the same preparation or theconcurrent administration of each agent by separate routes.

[0121] Prostate cancer therapy may in addition or as an alternativeinvolve hormone therapy. Such hormone therapy includes theadministration of gonadotrophic-releasing honrmones (GnRH) (also knownas luteinizing hormone-releasing hormones (LHRH), lupron, zolodex,casodox, flutamide and estrogen or analogs thereof.

[0122] Another prostate cancer therapy contemplated for use incombination with the Euphorbiaceae compounds is immunotherapy. Forexample, monoclonal antibodies including human antibodies and humanizednon-human antibodies directed to prostate cancer antigens may beadministered. Alternatively, vaccine compositions directed to prostatecancer agents may be used. Examples of prostate cancer antigens includebut are not limited to seminoprotein β-micro seminoprotein and isoformsand differentially acylated versions of isoforms and epitopes onfragments, carcinoembryonic antigen, chymotrypsin-like serine protease,members of the kallikrein family of proteins, prostate stem cell antigenand PSMA.

[0123] Still other therapies include exposure of the subjects oraffected areas on subjects to physical agents. An example of a physicalagent is radiation such as UV radiation, ionizing radiation orradioactive particles.

[0124] Furthermore, the administration of the above therapeutic agentsor treatments may also accompany interventionist procedures such assurgery or biopsy.

[0125] In addition, prostate cancer therapy may also involve thereduction in expression of certain genes associated with prostate cancersuch as metastatic sequences. Examples include the caveolin gene. Suchgenes or sequences may be down-regulated using, for example, antisensetechnology, sense suppression, co-suppression, ribozymes or moleculeswhich induce RNAi specific for the genes or their transcripts.Alternatively, or in addition, an anti-caveolin antibody orantigen-binding fragment thereof may be administered.

[0126] The present invention further extends to pharmaceuticalcompositions useful in treating a subject presenting with prostatecancer or the symptoms of prostate cancer. In this regard, the chemicalagents of the present invention can be used as actives for the treatmentor prophylaxis of prostate cancer or a related condition in a subject.The chemical agents can be administered to a patient either bythemselves, or in pharmaceutical compositions where they are mixed witha suitable pharmaceutically acceptable carrier alone or in combinationwith other compounds such as anti-cancer compounds.

[0127] Accordingly, the present invention also provides a compositionfor treatment and/or prophylaxis of prostate cancer or a related canceror condition in a subject, comprising one or more chemical agents of thepresent invention, together with a pharmaceutically acceptable carrierand/or diluent, and optionally one or more other active compounds.

[0128] The term “composition” includes an agent or other formulation.

[0129] Depending on the specific conditions being treated, chemicalagents may be formulated and administered systemically or locally.Topical and/or intralesional administration are particularly useful inthe practice of the present invention. Techniques for formulation andadministration may be found in “Remington's Pharmaceutical Sciences,”Mack Publishing Co., Easton, Pa., latest edition. Suitable routes may,for example, include oral, rectal, transmucosal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The agents may also be delivered at or near thesite of the tumor by catheter delivery into blood vessels supplying theprostate. For injection, the chemical agents of the present inventionmay be formulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks' solution, Ringer's solution, orphysiological saline buffer. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art. Intra-muscular andsubcutaneous injection is appropriate, for example, for administrationof immunomodulatory compositions and vaccines.

[0130] The chemical agents can be formulated readily usingpharmaceutically acceptable carriers well known in the art into dosagessuitable for oral administration. Such carriers enable the compounds ofthe invention to be formulated in dosage forms such as tablets, beads,pills, capsules, liquids, gels, syrups, slurries, suspensions and thelike, for oral ingestion by a patient to be treated. These carriers maybe selected from sugars, starches, cellulose and its derivatives, malt,gelatine, talc, calcium sulphate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffered solutions, emulsifiers,isotonic saline, and pyrogen-free water. Slow release formulations arealso contemplated by the present invention.

[0131] Formulations of active compounds in beads or other microparticlesare particularly useful for topical or intralesional administration andare specifically encompassed by the present. invention.

[0132] Pharmaceutical compositions suitable for use in the presentinvention include compositions wherein the active ingredients arecontained in an effective amount to achieve their intended purpose. Thedose of agent administered to a patient should be sufficient to effect abeneficial response in the patient over time such as a reduction in thesymptoms associated with prostate cancer or related condition in asubject. The quantity of the agent(s) to be administered may depend onthe subject to be treated inclusive of the age, sex, weight and generalhealth condition thereof. In this regard, precise amounts of theagent(s) for administration will depend on the judgement of thepractitioner. In determining the effective amount of the chemical agentto be administered in the treatnent or prophylaxis of a conditionassociated with prostate cancer or related condition, the physician, mayevaluate progression of the disorder. In any event, those of skcill inthe art may readily determine suitable dosages of the chemical agents ofthe present invention.

[0133] Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipopiiulic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0134] Pharmaceutical preparations for oral use can be obtained bycombining the active compounds with solid excipient, optionally grindinga resulting mixture, and processing the mixture of granules, afteradding suitable auxiliaries, if desired, to obtain tablets or drageecores. Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, maimitol, or sorbitol; cellulosepreparations such as., for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate. Such compositions may beprepared by any of the methods of pharmacy but all methods include thestep of bringing into association one or more chemical agents asdescribed above with the carrier which constitutes one or more necessaryingredients. In general, the pharmaceutical compositions of the presentinvention may be manufactured in a manner that is itself known, e.g. bymeans of conventional mixing, dissolving, granulating, dragee- making,levigating, emulsifying, encapsulating, entrapping or lyophilisingprocesses.

[0135] Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

[0136] Pharmaceutical compositions which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

[0137] Dosage forms of the chemical agents of the present invention mayalso include injecting or implanting controlled releasing devicesdesigned specifically for this purpose or other forms of implantsmodified to act additionally in this fashion. Controlled release of anagent of the present invention may be effected by coating the same, forexample, with hydrophobic polymers including acrylic resins, waxes,higher, aliphatic alcohols, polylactic and polyglycolic acids andcertain cellulose derivatives such as hydroxypropylmethyl cellulose. Inaddition, controlled release may be effected by using other polymermatrices, liposomes and/or microspheres, for example Captisol® orhyaluronic acid. Encapsulation is preferred for permitting controlledrelease of the subject chemical agents. Preferred vehicles forencapsulation include but are not limited to the microspheres described,for example, by Kanellalopoulou et al. (2000), Jain et al. (1998) andThomasin et al. (1998) and the liposomal deliver systems described, forexample, by Gabizon (2001), Kunisawa et al. (2001), Muggia (2001) andNishioka et al. (2001).

[0138] Chemical agents of the present invention may be provided as saltswith pharmaceutically compatible counterions. Pharmaceuticallycompatible salts may be formed with many acids, including but notlimited to hydrochloric, sulphuric, acetic, lactic, tartaric, malic,succinic, etc. Salts tend to be more soluble in aqueous or otherprotonic solvents that are the corresponding flee base forms.

[0139] For any chemical agent used in the method of the presentinvention, the therapeutically effective dose can be estimated initiallyfrom cell culture assays such as to reduce the growth of prostate cancercells ini vitio. For example, a dose can be formulated in animal modelsto achieve a circulating concentration range that includes the IC50 asdetermined in cell culture (e.g. the concentration of a test agent,which achieves a half-maximal inhibition of cancer cells). Suchinfonnation can be used to more accurately determine useful doses inhumans.

[0140] Toxicity and therapeutic efficacy of such chemical agents can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g. for determining the LD50 (the dose lethal to50% of the population) and the ED50 (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD50/ED50. Compounds that exhibit large therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a range of dosages for use in humans.The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED50 with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition (see for exampleFingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1 p1).

[0141] Dosage amount and interval may be adjusted individually toprovide plasma levels of the active agent which are sufficient tomaintain symptom-ameliorating effects. Usual patient dosages forsystemic administration range from 1-2000 mg/day, commonly from 1-250mg/day, and typically from 10-150 mg/day. Stated in terms of patientbody weight, usual dosages range from 0.02-25 mg/kg/day, conmonly from0.02-3 mg/kg/day, typically from 0.2-1.5 mg/kg/day. Stated in terms ofpatient body surface areas, usual dosages range from 0.5-1200 mg/m²/day,commonly from 0.5-150 mg/m²/day, typically from 5-100 mg/m²/day.

[0142] Alternately, one may administer the compound in a local ratherthan systemic manner, for example, via injection of the compounddirectly into a tissue, often in a depot or sustained releaseformulation. Furthermore, one may administer the drug in a targeted drugdelivery system, for example, in a liposome coated with tissue-specificantibody. The liposomes will be targeted to and taken up selectively bythe tissue. In cases of local administration or selective uptake, theeffective local concentration of the agent may not be related to plasmaconcentration.

[0143] The chemical agents of the present invention can also bedelivered topically. For topical administration, a compositioncontaining between 0.001-5% or more chemical agent is generallysuitable. Regions for topical administration include the skin surfaceand also mucous membrane tissues of the vagina, rectum, nose, mouth, andthroat. Compositions for topical administration via the skin and mucousmembranes should not give rise to signs of irritation, such as swellingor redness.

[0144] The topical coomposition may include a pharmaceuticallyacceptable carrier adapted for topical administration. Thus, thecomposition may take the form of a suspension, solution, ointment,lotion, sexual lubricant, cream, foam, aerosol, spray, suppository,implant, inhalant, tablet, capsule, dry powder, syrup, balm or lozenge,for example. Methods for preparing such compositions are well known inthe pharmaceutical industry.

[0145] In one embodiment, the topical composition is administeredtopically to a subject, e.g. by the direct laying on or spreading of thecomposition on the epidermal or epithelial tissue of the subject, ortransdermally via a “patch”. Such compositions include, for example,lotions, creams, solutions, gels and solids. Suitable carriers fortopical administration preferably remain in place on the skin as acontinuous film, and resist being removed by perspiration or immersionin water. Generally, the carrier is organic in nature and capable ofhaving dispersed or dissolved therein a chemical agent of the presentinvention. The carrier may include pharmaceutically-acceptableemollients, emulsifiers, thickening agents, solvents and the like.

[0146] The present invention also features a process for separatingditerpenes from a biomass containing same, said process comprisingcontacting the biomass with an aqueous solvent for a time and underconditions sufficient to extract the diterpenes into said solvent.

[0147] The aqueous solvent is preferably water.

[0148] Suitably, the biomass is derived from a plant, which ispreferably a member of the Euphorbiaceae family of plants or botanicalor horticultural relatives of such plants. Matter from the plant (e.g.foliage, stems, roots, seeds, bark, etc.) is preferably cut, maceratedor mulched to increase the surface area of the plant matter for aqueousextraction of the diterpenes.

[0149] The process preferably further comprises adsorbing the diterpenesto a non-ionic adsorbent, which is suitably a non-ionic porous syntheticadsorbent. Among the non-ionic porous synthetic adsorbents that can beused for the purposes of the present invention include, but are notrestricted to, aromatic copolymers mainly composed of styrene anddivinylbenzene, and methacrylic copolymers mainly composed ofmonomethacrylate and dimethacrylate. Such non-ionic porous syntheticadsorbents which comprise, as the basic structure, aromatic copolymersmainly composed of styrene and divinylbenzene include, for example,Diaion HP10, HP20, HP21, HP30, HP40, HP50, SP850, and SP205 (tradenames: Mitsubishi Chemical Corp.), and Amberlite XAD-2, XAD4, (tradenames: Rohm and Haas Co.). Examples of non-ionic porous syntheticadsorbent which comprise, as the basic structure, methacrylic copolymermainly composed of monometlhacrylate and dimethaciylate are DiaionHP2MG, Amberlite XAD-7, XAD-8 and XAD-16 and others.

[0150] Preferably, the process further comprises eluting diterpenes fromthe non-ionic adsorbent with water and water-soluble organic solvent(s).

[0151] The treatment may be conducted by a batch method using water andwater-soluble organic solvent(s) which dissolve diterpenes, or may alsobe conducted continuously or in batch using a column cliromatographymethod.

[0152] Examples of a water-soluble organic solvent which may be used inthe present invention are alcohols such as methanol, ethanol, n-propylalcohol, isopropyl alcohol, and tert-butanol, ethers such as dioxane andtetrahydrofuran, ketones such as acetone, amides such asdimethylformiamide, sulfur-containinig compounds such asdimethylsulfoxide. Two or more of such organic solvents may be mixed foruse. In addition, solvents less soluble in water, for example, alcoholssuch as n-butanol, esters such as methyl formate and methyl acetate, andketones such as methyl ethyl ketone may also be used to the extent thatit does not separate during development. Particularly preferredwater-soluble organic solvents are alcohols, in particular, methanol,ethanol, propyl alcohol, and the like. Furthermore, different kinds ofsolvent may also be used sequentially for development. Diterpenes can befurther purified using media and techniques which separate compounds onthe basis of molecular size and/or polarity. In a preferred embodimentof this type, the diterpenes are separated using Sephadex LH-20 resinand preferably using water and water-soluble organic solvent(s) fordevelopment.

[0153] The testing of the chemical agents of the present invention isconveniently conducted ussing in vivo animal models for prostate canceror related cancer. Any number of animal models are available. Forexample, surgical orthotopic implantation of histologically intactfragments of human prostate cancer may be transplanted toimmunodeficient animalssuch as rodents. See, for example, Hoffman(1999); Segawa et al. (2000).

[0154] There are also a range of in vitro models such as those describedin the Examples herein or by Anidjar et al. (2001).

[0155] The present invention is further described by the followingnon-limiting Examples.

EXAMPLE 1 Materials and Methods

[0156] Cells were cultured in RPMI1640 mediurn-10% w/v FCS in 5% v/v CO₂and 5% v/v oxygen. The latter reproduces physiological conditions and isconsidered useful in assessing the molecular responses of normal andtumor cells to drugs. Inhibition of cell growth was determined 5-7 daysafter drug treatment by assay of cell numbers with sulforhodamine B(SRB) in microtitre plates.

[0157] General cell signalling activity of the E. peplus compounds isquantitated by a sensitive assay which the present inventors havedeveloped, in which cells are simultaneously treated with the drug andinfected with a non-relicating adenovirus containing the CMV promoter,which drives expression of β-galactosidase (in place of Ela).Approximately 24 hours later, the β-galactosidase activity is measuredin an ELISA reader. The sensitivity of this assay (<ng/ml TPA) issufficient to measure bioactivity in blood and organs and serves as thebasis for comparison of structures and for translating doses determinedin the mouse to humans.

[0158] Primary, short-term cultures of adherent tumor cells areestablished from aspirates for drug treatments.

[0159] DNA flow cytometry (FACSCAN) is used for determining effects onthe cell cycle.

[0160] Microarrays of 4000 human cDNA sequences spotted on microscopeslides are hybridized with fluorescent-labelled cDNA fromreverse-transcribed cellular MRNA and quantitated as described byBowtell (1999).

EXAMPLE 2 Pre-treatment of Human Tumor Cells in Culture with DiterpeneEsters Potentiates Selective Killing by Untreated Leuktocytes

[0161] The question of whether drug treatment of the target tumor cellscauses them to become susceptible to effector cells of the immune systemwas addressed as follows.

[0162] Leukocytes obtained by lysis of human peripheral blood were addedto 5000 MM96L human melanoma cells or 7000 neonatal foreskin fibroblastsper microtitre well at effector: target ratios of 1000, 100 and 10:1.The target cells had been treated with 60 ng/mL PEP008 for 20 hrbeforehand, and washed and the medium replaced before the leukocyteswere added. After 48 hr incubation with the leukocytes the cultures werewashed and labelled with [3H]-thymidine for 2 hr. At 100:1 ratio ofeffector:target cells, the melanoma cells showed 12% survival withPEP008 whereas the normal fibroblasts had 100% survival. Untreatedleukocytes had no effect on cell survival.

[0163] This result showed that the drugs also act by making tumor cellsspecifically sensitive to lysis by the imunue system.

EXAMPLE 3 Effect of E. peplus Sap on Prostate Cancer Cells

[0164] The ability of E. peplus sap to kill prostate cancer cellsselectively was assessed by comparing the effect of the sap on prostatecancer cell lines and on normal fibroblasts. Three prostate cancer celllines were used; PC-3 and DU145 are hormone resistant prostate cancercell lines and LNcap is a hormone-sensitive prostate cancer cell line.

[0165] The prostate cancer cell lines or normal fibroblasts weresuspended to a concentration of 5 X 10³ cells/well in RPMI1640 tissuecultmue medium containing 10% w/v FCS, volume 0.1 ml in microtitreplates.

[0166] The cells were incubated for 6 hr at 37° C., followed by theaddition of E. peplus crude sap (approximately 110 mg dry solids per ml)to the final dilutions, as shown in FIG. 1. After 5 days, cells werescored visually for survival morphology changes and survival was alsoassessed by ³H-thymidine incorporation into cell mass. The results areexpressed as percentages of cell survival relative to the control (cellswithout drug treatment).

[0167] It can be seen that there was a concentration-dependentinhibition of all three prostate cancer cell lines, whereas normalfibroblasts remained unaffected or increased in number of concentrationsof sap below 100 μg/ml.

EXAMPLE 4 The in vitro Activity of the Pure Compounds

[0168]E. peplus compounds already known to be active on other tumortypes are tested for growth inhibition of the three prostatic cancercell lines used in Example 1 and against primary cultures of tumor cellsobtained by aspiration of bone marrow metastases from patients. Threepatient samples are considered sufficient to confirm potency andselectivity in humans; approximately 20 suitable patients, who haveaccessible bone metastases in the spine, but are well enough to undergothe procedure, are available in Brisbane each year.

[0169] The E. peplus compounds are compared to TPA and Taxol as regardspotency and selectivity against tumor cells.

[0170] The two best candidate compounds, wvhich are shown to be potentand selective compared with activity against normal fibroblasts andbladder endothelial cells are then evaluated in xenografts of tumorcells in nude mice. This model is widely used in the art (see, forexample, Agus et al., 1999; El Etreby et al., 2000; Navone et aL, 1998)and is sufficient to evaluate drugs for treatment of metastatic disease.The diterpenes are lipophilic and are expected to be capable of reachingthe bone marrow.

[0171] Moreover, less polar derivations of the ingenane, pepluane andjatrophane structures are readily prepared, for example, by acylation ofthe C₈ hydroxyl of the jatrophanes.

EXAMPLE 5 Optimizing the use of the E. peplus Compound

[0172] It is expected that, as found by Han et al. (1998) for TPA and byothers for Taxol, the drug dose can be increased in the presence of ananti-inflammatory agent such as prednisolone. The optimum level ofprednisolone is determined in the mouse model and then the dose ofditerpene increased, in order to obtain maximum non-toxic daily dosingfor at least three days.

[0173] On the basis of the anticipated cell cycle arrest by E. peplusditerpenes and from results with TPA, it is expected that a range ofcurrently available drugs such as hydroxyurea, topoisomerase inhibitorsand other PKC inhibitors will synergize the action of the E. peplusditerpenes if administered at a suitable time. This is assessed in twoways. The candidate drugs are given to cultured prostatic cancer cells(cell lines and fresh tumnor cells) at different temporal combinationswith E. peplus diterpenes, to ascertain synergism. Second, cDNAmicroarray profiling is carried out, preferably with fresh cultures andcDNA amplification used to determine the changes in gene expressioninduced by these drugs in prostate cancer cells. Changes that areexploited pharmacologically are followed up in vitro and then in vivo.

[0174] In a third approach, the most active diterpenes are chemicallylinked to methylene diphosphonate (MDP), a bone-seeking compoundcommonly used as an imaging agent (Norris et al., 1999) and the activityof the conjugate tested against prostate cancer cells. The diterpenesare aliphatic esters which should be capable of an exchange reactionwith a suitable derivative of MDP and would then be released by esteraseactivity in the bone marrow. The diterpenes have been found to be stablein human plasma and are not toxic to lymphoid cells. Combining physicaland biological selectivity in this way may be highly advantageous.

EXAMPLE 6 Clinical Trial

[0175] It is estimated that 200-300 new cases of advanced prostatecancer present each year in Brisbane and the power of evaluation by theprostate specific antigen (PSA) test (Scliroder et al., 2000) is suchthat only 20 patients will be required in the first instance if a 50%drop in PSA is taken as an indicator of response. Sterile diterpene andanti-inflanmiatory are administered i.v., essentially as described byHan et al. (1998) for TPA except that the first dose is ⅓ of thebioactivity of the amount of TPA used by Han et al. (1998) (based on therange of in vitro and in vivo data available). This dose is subsequentlyescalated. Vital signs are monitored closely during the first 48 hr.Blood profiles, including PSA, are measured weekly for four weeks, atwhich time a decision is made whether to repeat the treatment. A similarprotocol is used for experiments involving intralesional injections andfor the use of slow release formulations, beads or capsules.

[0176] The level of active diterpene in the blood is detected bybioassay on a tumor cell line as assessed by induction of6-galactosidase due to transcriptional activation of the CMV promoter;the sensitivity of the assay is <1 ng/ml, which can be further einancedby solvent extraction, concentration and HPTLC, if necessary. Thechanges in PSA (natural log PSA; Schroder et al., 2000; Vollmer et al.,1999) and other clinical indicators are correlated to determine theoutcome of the trial. A reduction in PSA of >50% over three months issought; however, pain relief, stabilization of disease and bone scansare also considered.

EXAMPLE 7 Topical Treatment of DU145Prostate Tumor inNude^((nu-/nu-))Mice with PEP003

[0177] To assess whether the E. peplus compounds reduce tumors in mice,a DU145 prostate tumor was implanted into nude^((nu-/nu-)) mice andtreated with PEP003 (see Table 1). Ten mice were divided up into twogroups of four mice and six mice, a control group and a treatment group,respectively. In both groups, each mouse was injected (s.c.), with 1×10⁶(50 μl) DU145 prostate tumor cells into each of two sites. After 20days, the tumor was visible (4 mm³). In the control group, all tumorsites were treated by a single topical application of 2 μl of 100% v/vacetone. In the treatment group, all tumor sites were treated by asingle topical application of 2 μl of PEP003 in 100% v/v acetone,containing approximately 50 μg of PEP003. The mice were observed fornine weeks and the tumor size measured. Control mice were sacrificedbefore tumor burden became excessive.

[0178] The results (FIG. 2) show a rapid increase of DU145 prostatetumor in the control group, to an average tumor size of 167 mm³, 46 dayspost inoculation. The results also show that treatment of DU145 prostatetumor by topical application of PEP003 cured the tumor, withoutre-growth after 62 days.

[0179] The data clearly show that topical application of PEP003 ontosubcutaneous DU145 prostate tumors in nude^((nu-/nu-)) mice causes tumorcure.

EXAMPLE 8 Topical Treatment of PC-3 Prostate Tumor innude^((hu-/nu-))Mice with PEP003

[0180] To assess whether the E. peplus compounds reduce tumors in mice,PC-3 prostate tumor was implanted into nude^((nu-/nu-)) mice and treatedwith PEP003 (see Table 1). Thirteen mice were divided up into two groupsof five mice and eight mice, a control group and a treatment group,respectively. In both groups, each mouse was injected (s.c.), with 1×10⁶(50 μl) PC-3 prostate tumor cells into each of two sites. After threedays, the tumor was visible (4 mm³). In the control group, all tumorsites were treated by a single topical application of 2 μl of 100% v/vacetone. In the treatment group, all tumor sites were treated by asingle topical application of 2 μl of PEP003 in 100% v/v acetone,containing approximately 50 μg of PEP003. The mice were observed forfive weeks and the tumor size measured. Control mice were sacrificedbefore tumor burden became excessive.

[0181] The results (FIG. 3) show a rapid increase of PC-3 prostate tumorin the control group, to an average tumor size of 136 mm³, 37 days postinoculation. The results also show that treatment of PC-3 prostatetumors by topical application of PEP003 cured the tumor, withoutre-growth after 37 days.

[0182] The data clearly show that topical application of PEP003 ontosubcutaneous PC-3 prostate tumors in nude^((nu-/nu-)) mice causes tumorcure.

EXAMPLE 9 Intralesional Treatment of PC-3 Prostate Tumor inNude^((nu-/nu-)) Mice with PEP003

[0183] To assess whether the E. peplus compotmds reduce tumors in mice,PC-3 prostate tumor was implanted into nude^((nu-/nu-)) mice and treatedwith PEP003 (see Table 1). Ten mice were divided up into two groups ofsix mice and four mice, a control group and a treatment group,respectively. In both groups, each mouse was injected (s.c.), with 1×10⁶(50 μl) PC-3 prostate tumor cells into each of two sites. After sixdays, the tuimor was visible (1 mm³). In the control group, all tumorsites were treated by a single intralesional injection of 10% v/vacetone in saline. In the treatment group, all tumor sites were treatedby a single intralesional injection of 10% v/v acetone in saline (50μl), containing approximately 6.25 μg of PEP003. The mice were observedfor 19 weeks and the tumor size measured. Control mice were sacrificedbefore tumor burden became excessive.

[0184] The results (FIG. 4) show a rapid increase of PC-3 prostate tumorin the control group, to an average twfor size of 100 mm³, 34 days postinoculation. The results also show that treatment of PC-3 prostatetumors by intralesional injection of PEP003 cured the tumor, withoutre-growth after 131 days.

[0185] The data clearly show that intralesional injection of the PEP003onto subcutaneous PC-3 prostate tumors in nude^((nu-/nu-)) mice causestumor cure.

EXAMPLE 10 Intralesional Treatment of DU145Prostate Tumor innude^((nu-/nu-))Mice with PEP003

[0186] To assess whether the E. peplus compounds reduce tumors in mice,DU145 prostate tumor was implanted into nude^((nu-/nu-)) mice andtreated with PEP003 (see Table 1). Six mice were divided up into twogroups of four mice and two mice, a control group and a treatment group,respectively. In both groups, each mouse was injected (s.c.), with 1×10⁶(50 μl) DU145 prostate tumor cells into each of two sites. After 20days, the tumor was visible (2 mm³). In the control group, all tumorsites were treated by a single intralesional injection of 10% v/vacetone in saline. In the treatment group, all tumor sites were treatedby a single intralesional injection of 10% v/v acetone in saline (50μl), containing approximately 2.5 μg of PEP003. The mice were observedfor nine weeks and the tumor size measured. Control mice were sacrificedbefore tumor burden became excessive.

[0187] The results (FIG. 5) show a rapid increase of DU145 prostatetumor in the control group, to an average tumor size of 167 mm³, 46 dayspost inoculation. The results also show that treatment of DU145 prostatetumors by intralesional injection of PEP003 cured the tumor, withoutre-growth after 62 days.

[0188] The data clearly show that intralesional injection of PEP003 ontosubcutaneous DU145 prostate tumors in nude^((nu-/nu-)) mice causes tumorcure.

EXAMPLE 11 Synergisitic Combination of PEP005, PEP006 or PEP008 withCisplatin oi Suberic Dihydroxamic Amino Acid on DU145 Prostate CancerCell Cytotoxicity

[0189] DU145 prostate cancer cells were treated with a drug combinationcomprising a purified preparation of an angeloyl-substitued ingenaneselected from PEP005, PEP006 or PEP008 and a chemotherapeutic agentselected from cisplatin or suberic dihydroxamic amino acid (SBHA) toassess whether such combination displays synergistic effects on prostatecancer cytotoxicity.

[0190] The prostate cancer cells were treated with (A) PEP006 andcisplatin, (B) PEP008 and cisplatin, (C) PEP005 and SBHA, (D) PEP008 andSBHA and (E) PEP005 and cisplatin for 24 hr after which the medium waschanged and the cells permitted to grow in the presence of ³H-thymidinefor five days. The percentage cell survival was determined by measuringthe incorporation of ³H-thymidine in the cells.

[0191] The results presented in FIGS. 6A to 6E indicate thatcombinations of cisplatin or SBHA together with PEP005, PEP006 or PEP008produce greater cytotoxicity compared to the additive cytotoxicity ofthe compounds when administered alone and are, therefore, synergisticcombinations.

EXAMPLE 12 Methods for Obtaining a Low-Chlorophyll, hydrophobic Fractionfrom E. peplus and Other Plant Species

[0192] Standard methods for the isolation of hydrophobic compounds fromplants involve alcoholic extraction of the whole plant. This produces anextract containing chlorophyll and other hydrophobic substances from theleaves that interfere with subsequent purification of compounds bysolvent extractions and chromatography. This is a particular problem inisolating highly bioactive diterpenes from members of the Euphorbiaceaefamily, due to co-migration with chlorophyll on silica gelchromatography. Two methods, both of which can be scaled up foreconomical, commercial production, have been developed to overcome thisproblem, as described in the present Example and in Example 14.

[0193] Fresh E. peplus plants (17 kg) were chopped and soaked in 150litres of water at 4° C. for 20 hr. The water was pumped through 50 and100 mesh sieves, filtered through 5 and 2 micron filters and thenrecirculated through a 100 mm diameter column of Amberlite XAD-16 (1.5kg, conditioned successively with ethyl acetate, methanol and water) at4° C. (approximately 1.2 L/min) for 72 hr. Adsorption of bioactivity tothe resin was found to be virtually complete within 20 hr.

[0194] The resin was then washed successively with water and 50% v/vmethanol, then eluted with 1 L of methanol, followed by 2×1 L acetone.The eluates were evaporated and combined to give approximately 7 g of athick oil. This was shown by HPTLC to be substantially free ofchlorophyll and to contain the desired ingenane esters which were thenpurified as described below.

[0195] The ability to extract diterpene esters from chopped plants inwater was surprising given their relative hydrophobicity and waterinsolubility. A variety of manual (cutting with scissors) and mechanical(rotary cutters, motor-driven mulcher) plant maceration methods weresuccessful, as was extraction at room temperature. Adsorption to theXAD-16 could be achieved by stirring the resin with the filtered orunfiltered water extract and then pouring off the latter. Filtrationcould also be carried out with mininal loss of bioactivity usingdiatomaceous earth, or membrane filters (220-650 microns). XAD-7 andXAD-4 were as effective as XAD-16.

[0196] The hydrophobic adsorbent polyamide (ICN Biomedical ResearchProducts) was also used to trap the diterpenes from water; it had theadvantage of allowing the diterpene esters to be selectively eluted with50-80% v/v methanol, thus separating theim from inactive, hydrophobiccompounds, which remained on the column.

EXAMPLE 13 Method for Separation of Ingenane Esters From OtherDiterpenes

[0197] The following method is based upon the surprising discovery thatthe stems of E. peplus contain approximately 90% of the bioactivediterpenes and significantly less chlorophyll compared with the leaves.

[0198] The plants are dried in air, shaken to remove the leaves and thestems compressed and covered with an equal weight of methanol for 24hir. The solvent is then poured off, evaporated to dryness under reducedpressure and the residue dissolved in methanol for chromatography onSephadex LH-20 as described below. This method is also suitable forisolation of low-chloroplhyll fractions from other plant species.

[0199] A solution of crude methanol extract from E. peplus in 4 mL 90%v/v ethanol was loaded onto a 25 mm ×1000 mm column and eluted with 90%v/v methanol. Fractions (4 mL) were analyzed by HPTLC (silica gel,developed with 4:1 toluene: acetone and heated with phosphoric acid at110° C. for 15 min). Typically, fractions 54-63 contained jatrophane andpepluane esters and fractions 64-77 the ingenane esters, thus achievingsatisfactory separation. Bioactivity, as judged by induction of bipolarmorphology in the human melanoma cell line MM96L, was retained as, forexample, disclosed in International Patent Application No.PCT/AU98/00656.

[0200] This separation was surprising because the polarity of theingenane esters as judged by HPTLC on silica completely overlapped therange shown by the jatrophane and pepluane esters.

EXAMPLE 14 Process for the Purification of Diterpene Esters from E.peplus

[0201] Crude extracts obtained by the methods according to Examples 17or 18 above, or by ether extraction of latex, were fractionated bySephadex HL-20 chromatography (as above). Appropriate fractions from thelatter were combined, the methanol evaporated under reduced pressure andthe remaining water removed by freeze-drying or by ether extraction.This sample (200 μL of 100 mg/mL in methanol per injection) wasfractionated by HPLC on a Phenomenex Luna 250×10 mm C18 column with aPhenomenex guard column in 70-100% v/v methanol at 2 mL/min, withdetection at 230 nm. Jatrophane and pepluane esters appeared at 25-42min, PEP005 at 42-44 min, PEP008 at 46-50 min, and PEP006 at 50-54 min.Similar types of separation have been obtained by HPLC on C3 and C₈columns.

[0202] Fractions pooled from repeated runs were evaporated to dryness(rotary evaporater or freeze dryer) and stored in acetone at −20° C.under argon or nitrogen.

[0203] Speculative procedures for synthesis of bisphosphonatesubstituted ingenanes.

EXAMPLE 15 Synthesis of 20-Chloro-20-Deoxyingenol 3,5-Dibenzoate fromIngenol—Scheme 1

[0204] Ingenol can be converted to 20-chloro-20-deoxyingenol3,5-dibenzoate by the procedure reported in Appendino et al. (1999).Thus, ingenol can be converted to ingenol 20-trityl ether by treatmentwith trityl chloride and 4-(N,N-dimethylamino)pyridine in dry pyridine.Ingenol-20-trityl ether can be converted to ingenol 3,5-benzoate bytreatment with benzoic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride anddimethyl-aminopyridine in dichloromethane followed by reaction withmethanolic perchloric acid. Ingenol 3,5-dibenzoate can be converted to20-chloro-20-deoxyingenol 3,5-dibenzoate by reaction withhexachloroacetone and triphenylphosphine in dry dichloromethane.

EXAMPLE 16 Synthesis of 20-Chloro-20-Deoxyingenol 3,5-dibenzoate fromIngenol 3-angelate

[0205] Ingenol 3-angelate extracted from Euphorbia species could beconverted to 20-chloro-20-deoxyingenol 3-angelate 5-benzoate by themethod of Example 15.

EXAMPLE 17 Synthesis of 20-Chloro-20-Deoxyingenol 3,5-dibenzoate fromIngenol—Scheme 2

[0206] Ingenol is reacted with p-toluenesulphonic acid hydrate andacetone to give ingenol-5,20-acetonide according to the procedure ofOpferkuch et al. (1981). Ingenol-5,20-acetonide is converted to theingenol 3-acylate by treatment with the appropriate acyl chloride and4-(N,N-dimethylamino) pyridine or pyridine in toluene or benzene, ortreatment with the appropriate acid, an alkylpyridinium salt andtributylamine in toluene then treatment with methanolic perchloric acidaccording to the procedure of Sorg et al. (1982). The ingenol 3-acylatecould be converted to the 20-chloro-20-deoxyingenol 3-acylate 5-benzoateby the method of Example 15.

EXAMPLE 18 Synthesis of 20-Chloro-20-Deoxyingenol 3,5-Dibenzoate fromIngenol—Scheme 3

[0207] Ingenol can be converted to ingenol-3,4-acetonide by treatmentwith 4-toluenesulphonic acid hydrate and acetone to giveingenol-3,4:5,20-diacetonide followed by treatment with perchloric acidin methanol or zinc bromide in dichloromethane and methanol according tothe method of Opferkuch et al. (1981). Ingenol-3,4-acetonide could beconverted to ingenol-3,4-acetonide-20-trityl ether by treatment withtrityl chloride and 4-(N,N-dimethylamino) pyridine in dry pyridine,acylated in an analogous manner to that described in Example 1 orExample 3 to give the ingenol-3,4-acetonide-20-trityl ether 5-acylatethen treated with methanolic perchloric acid according to the method ofExample 15 or Example 18 to give the ingenol 5-acylate. The ingenol5-acylate could then be converted to the ingenol-3,4-acetonide 5-acylateby treatment with 4-toluenesulphonic acid hydrate and acetone accordingto the method of Opferkuch et al. (1981). The ingenol-3,4-acetonide5-acylate could be converted to the 20-chloro-20-deoxy-3,4-acetonide5-acylate by the method of Example 15.

EXAMPLE 19 Preparation of TetraalkylPhthalimido-1-Hydroxyalkylbisphosphonates

[0208] Tetraallcyl phthalimido-1-hydroxyalkylbisphosphonates can beprepared by the method of El Manouni et al. (1989). These could beconverted to the corresponding tetraalkylamino-1-hydroxyalkylbisphosphonates by standard treatment with hydrazinehydrate in ethanol.

EXAMPLE 20 Synthesis of Bisphosphonic Acid Derivatives of Acylingenols

[0209] 20-chloroingenol acylates from Examples 17-20 could be reactedwith 1,1-bis(dialkoxyphosphoryl)-1-hydroxyalkylamines,triphenylphosphine, diethylazodi-carboxylate and tetrahydrofuran to give20-[bis(dialkoxyphosphoryl)hydroxyalkylamino]-20-deoxy-3-O-acylingenolsand20-[bis(dialkoxyphosphoryl)hydroxyalkylamino]-20-deoxy-5-O-acylingenolsaccording to the procedure of Appendino et al (1999).20-[Bis(dialkoxyphosphoryl) hydroxyalkylamino]-20-deoxy-3-0-acylingenols and 20-[bis(dialikoxyphosphoryl)hydroxyalkylanino]-20-deoxy-5-O-acylingenols could be converted to thecorresponding20-[bis(dihydroxyphosphoryl)hydroxyallcylamino]-20-deoxy-3-O-acylingenolsand20-[bis(dihydroxyphosphoryl)hydroxyalkylamino]-20-deoxy-5-O-acylingenolsby treatment with bromotrimethylsilane or iodotrirnethylsilane andsolvolysis with alcohol or water according to Lecouvey et al. (2000) andreferences therein. The bisphosphonic acids could be converted to theappropriate salts by careful titration with an inorganic base, forexample, sodium hydroxide.

EXAMPLE 21 Synthesis of Ingenol-3-Acylate-20-Trityl Ethers fromIngenol-3-acylates

[0210] Ingenol-3-acylates could be converted to the correspondingingenol-3-acylate-20-trityl ethers by the method of Example 17.Ingenol-3-acylate-20-trityl ethers could be converted to5-(chloromethylcarbonyloxy)ingenol-3-acylate-20-trityl ethers or5-(bromomethyl-carbonyloxy) ingenol-3-acylate-20-trityl ethers byreaction with chloroacetyl chloride or bromoacetyl chloride and4-(N,N-dimethylamino)pyridine in pyridine and dry ether according to theprocedure of Nangia et al (1996).5-(Chloromethylcarbonyloxy)ingenol-3-acylate-20-trityl ether or5-(bromomethylcarbonyloxy)ingenol-3-acylate-20-trityl ethers could beconverted to5-[bis(dialkoxyphosphoryl)hydroxyalkylaminomethylcarbonyloxy]-ingenol-3-acylate-20-tritylethers by the method of Example 6 and then converted to5-[bis(dialkoxyphosphoryl)hydroxyalkylaminomethylcarbonyloxy]ingenol-3-acylates by the method ofExample 15. These could then be converted to [bis(dihydroxy-phosphoryl)hydroxyalkylaminomethylcarbonyloxy]ingenol-3-acylates or salts thereofby the method of Example 20.

EXAMPLE 22 Synthesis of-[bis(dihydroxyphosphoryl)Hydroxyalkylamino-Methylcarbonyloxy]Ingenols

[0211] (9S)-9-Deoxo-9-hydroxyingenol-3,4:5,20-diacetonide can beprepared from ingenol-3,4:5,20-diacetonide by reduction with lithiumaluminium hydride in tetrahydrofuran and(9R)-9-deoxo-9-hydroxyingenol-3,4:5,20-diacetonide can be prepared fromingenol-3,4:5,20-diacetonide by reduction with sodium in 2-propanol andether according to the procedure of Bagavathi et al. (1991). (9S)- or(9R)-9-Deoxo-9-hydroxyingenol-3,4:5,20-diacetonide could be converted to(9S)- or (⁹R)-9-deoxo-9-(chloromethyl-carbonyloxy)ingenol-3,4:5,20-diacetonide or (9S)- or(9R)-9-deoxo-9-(bromomethyl-carbonyloxy) ingenol-3,4:5,20-diacetonide byreaction with chloroacetylchloride or bromoacetylchloride and4-(N,N-dimethylamino)pyridine in pyridine and dry ether according to theprocedure of Nangia et al. (1996). (9S)- or(9R)-9-Deoxo-9-(chloromethylcarbonyloxy) ingenol-3,4:5,20-diacetonide or(9S)- or (9R)-9-deoxo-9-(bromomethylcarbonyloxy)ingenol-3,4:5,20-diacetonide could be converted to the corresponding(9S)- or(9R)-9-deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalkylamino-methylcarbonyloxy]ingenol-3,4:5,20-diacetonideby the method of Example 6. (9S)- or(9R)-9-Deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalcylaminomethylcarbolyloxy]ingenol-3,4:5,20-diacetonidecould be treated with methanolic perchloric acid followed by4-toluenesulphonic acid hydrate to give (9S)- or(9R)-9-deoxo-9-[bis(dialkoxyphosphoryl)-hydroxyalkylaminomethylcarbonyloxy]ingenol-5,20-acetonideaccording to the method of Example 17. This in turn could be convertedto (9S)- or (9R)-3-acyl-9-deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalkylaminomethylcarbonyloxy]ingenol -5,20-acetonides then (9S)-or(9R)-3-acyl-9-deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalkylaniinomethyl-carbonyloxy]ingenolsby the method of Example 19. These could then be converted into (9S)- or(9R)-3-acyl-9-deoxo-9-[bis(dihydroxyphosphoryl)hydroxyallalninomethyl-carbonyloxy]ingenolsand salts thereof by the method of Example 20.

EXAMPLE 23 Acylated Tetraalkyl Bisphosphonate Derivatives of Ingenol

[0212] Tetraalkyl bisphosphonate derivatives of ingenol can be furtheracylated on any free hydroxyl groups selected from the 3-OH, 5-OH and20-OH by treatment with an appropriate acyl chloride and4-(N,N-dimethylaminopyridine) or pyridine in toluene or benzeneaccording to the procedure of Sorg et al. (1982), then converted to thebisphosphonic acid derivatives of ingenol or salts thereof by the methodof Example 20.

EXAMPLE 24 Preparation of Deoxyingenol 3,5-Diacylates from20-Deoxy-17-Hydroxy-Ingenol

[0213] 20-Deoxy-17-hydroxy-ingenol obtained by hydrolysis of esters fromEuphorbia species could be converted to 20-deoxy-17-hydroxy-ingenol3,5-diacylate 17-trityl ethers then to 20-deoxy-17-hydroxy-ingenol3,5-diacylates and 17-chloro-20-deoxyingenol 3,5-diacylates by themethod of Example 15. These could then be converted to17-[bis(dihydroxyphosphoryl) hydroxyallcylamino]-20-deoxyingenol3,5-diacylates and salts thereof by the method of Example 20.

EXAMPLE 25 Preparation of Bisphosphonate Derivatives of Acylingenols

[0214] 17-Hydroxyingenol obtained by hydrolysis of esters from Euphorbiaspecies could be converted to, 17-hydroxyingenol-3,4:5,20-diacetonide bythe method of Example 18 and thence to17-chloroingenol-3,4:5,20-diacetonide by the method of Example 15. Thiscould then be converted to 17-chioroingenol by treatment with methanolicperchloric acid and converted to 17-chloroingenol-5,20-acetonide then to3-acyl-17-chloroingenols by the method of Example 17.3-Acyl-17-chloroingenols could be converted to17-[bis(dihydroxyphosphoryl)hydroxyallcylamino]-20-deoxy-3-O-acylingenols and salts thereof by themethod of Example 20. Further acylation of these could be achieved bythe method of Example 23.

[0215] Those skilled in the art will appreciate that the inventiondescribed herein is susceptible to variations and modifications otherthan those specifically described. It is to be understood that theinvention includes all such variations and modifications. The inventionalso includes all of the steps, features, compositions and compoundsreferred to or indicated in this specification, individually orcollectively, and any and all combinations of any two or more of saidsteps or features.

BIBLIOGRAPHY

[0216] Agus et al., Cancer Res. 59; 4761-4764, 1999.

[0217] Anidjar et al., Prostate 46: 2-10, 2001.

[0218] Antalis et al., J. Exp. Med. 187: 1799-1811, 1998.

[0219] Appendino et al., Eur. J. Org. Chem. 3413-3420, 1999.

[0220] Bagavathi et al.,Z. Naturforsch 46b: 1425-1433, 1991.

[0221] Botwell, Nature Genet 21: 25-32, 1999.

[0222] Bushnell et al., Nucl. Med. Commun. 20: 875-881, 1999.

[0223] Christenson et al., Endothelium 7: 75-82, 1999.

[0224] El Etreby et al., Prostate 42: 99-106, 2000.

[0225] Elliott et al., Vaccine 17: 2009-2019, 1999.

[0226] El Manouni et al., Phosphorus Sulfur and Silicon 42: 73-83, 1989.

[0227] Evans & Osman, Nature 250: 348, 1974.

[0228] Fatope et al., J. Med. Chem. 39: 1005-1008, 1996.

[0229] Gabizon, Canzer Invest. 19): 424-436, 2001.

[0230] Gonzalez et al., Melanoma Res. 9: 599-606, 1999.

[0231] Greaves and Wall, Lancet 348): 938-940, 1996.

[0232] Gundidza and Kufa, Centr. Afr. J Med. 38: 444-447, 1992.

[0233] Han et al., Proc. Natl. Acad. Sci. USA 95: 5357-5361, 1998.

[0234] Hecker “Cocarcinogens from Euphorbiaceae and Thymeleaceae” in“Symposium on Pharmacognosy and Phytochemistry”, 147-165, (Wagner etal., eds., Springer Verlag, 1970).

[0235] Hoffmann, Invest. New Drugs 17: 343-359, 1999.

[0236] Hohmann et al., J. Nat. Products 6: 107-109, 1999.

[0237] Horsmanheimo et al., J. Allergy Clin. Immunol. 98: 408-411, 1996.

[0238] Imai et al., Anticancer Res. 14: 933-936, 1994.

[0239] Jain et al., Drug Dev. Ind. Pharm. 24: 703-727, 1998.

[0240] Kanellakopoulou et al., Drugs 59 1223-1232, 2000.

[0241] Kunisawa et al., Gan To Kagaku Ryoho 28): 577-583, 2001.

[0242] La Linn et al., J. Gen. Virol. 77: 407-412, 1996.

[0243] Lecouvey and Leroux, Heteroatom Chemistry 11: 556-561, 2000.

[0244] Marks et al., Int. J. Cancer 53(4): 585-590, 1993.

[0245] Matsushita et al., Int. J. Hematol. 72(1): 20-7, 2000.

[0246] Miller et al., J. Am. Acad. Dermatol. 30(5): 774-778, 1974.

[0247] Mollinedo, Immunol. Today 20(12): 535-7, 1999.

[0248] Muggia, Curr. Oncol. Rep. 3: 156-162, 2001.

[0249] Murali-Krishna et al., Immunity 8: 177-187, 1998.

[0250] Nangia et al., J. Chem. Res. Miniprint 7: 1716-1730, 1996.

[0251] Navone et al., Cancer Metastasis Rev. 17: 361-371, 1999.

[0252] Nishioka et al., Adv. Drug Deliv. Rev. 47): 55-64, 2001.

[0253] Norris et al., Clin. Nucl. Med. 24(11): 905-907, 1999.

[0254] Oksuz et al., Phytochemistry 42: 473-478, 1996.

[0255] Opferkuch et al., Z. Naturforsch 36b: 878-887, 1981.

[0256] Post et al., Int, J. Epidemiol. 28: 403-408,1999.

[0257] Schroder et al., Prostate 42: 107-115, 2000.

[0258] Segawa et al., Prostate 45: 335-340, 2000.

[0259] Sorg and Hecker, Z. Naturforsch 37b: 748-756, 1982.

[0260] Starvic and Stolz, Food Cosmet. Toxicol. 14: 141, 1976.

[0261] Steinkamp et al., Science 215. 64-66, 1982.

[0262] Thomasin et al., J. Pharm. Sci. 87: 259-268, 1998.

[0263] Tobiume et al., J. Gen. Virol. 79: 1363-1371, 1998.

[0264] Vollmer and Montana, Clin. Cancer Res 5(9): 2476-2484, 1999.

1. A method for the treatment or prophylaxis of prostate cancer or arelated cancer or condition in a subject, said method comprising theadministration to said subject of a symptom-ameliorating effectiveamount of a chemical agent obtainable from a plant of t h eEuphorbiaceae family or a derivative or chemical analog thereof whichchemical agent is a diterpene selected from compounds of the ingenane,pepluane and jatrophane families and which chemical agent or derivativeor chemical analog is represented by any one of the general formulae(a - (V):-

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefmed by said atoms is saturated or unsaturated, including epoxides andtluoepoxides; A-T are independently selected fiom hydrogen, R₁, R₂, R₃,F, Cl, Br, I, CN, OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁,SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂,(C=X)R₃ or X(C=X)R₃ where X is selected from sulfur, oxygen andnitrogen; R₁ and R₂ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ allcoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁, SR₁,NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂,SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂]alkyl; R₃ is selected fromR₁, R₂, CN, COR₁, CO₂R₁, OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁,SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃,B(R₁)₂; A connected to B (or C), D (or E), R (or Q), P (or O) or S (orT) is a selection of C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic rings further substituted by R₃,(C=X)R₃ and X(C=X)R₃, including epoxides and thioepoxides; J connectedto I (or H), G (or F), K (or L), M (or N) or S (or T) is a selection ofC₁-C₈ disubstituted (fused) saturated and unsaturated carbocyclic orheterocyclic rings further substituted by R₃, (C=X)R₃ and X(C=X)R₃,including epoxides and thioepoxides; D (or E) connected to B (or C) or G(or F); I (or H) connected to G (or F); P (or O) connected to R (or Q)or M (or N); K (or L) connected to N (or M) is a selection of C₁-C₈disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic rings substituted by R₃, (C=X)R₃ and X(C=X)R₃, includingepoxides and thioepoxides; B and C, D and E, R and Q, P and O, I and H,G and F, K and L M and N or S and T are =X where X is selected fromsulfur, oxygen, nitrogen, NR₁R₂, and =Cr₁R₂

wherein: n is 0-10 atoms seleeted from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A′-T′ are independently selected from hydrogen, R₄,R₅, R₆, F, Cl, Br, I, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅, CONR₄R₅, N(=O)₂,NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃,P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂, (C=X)R₆ or X(C=X)R₆ where X is selectedfrom sulfur, oxygen and nitrogen; R₄ and R₅ are each, independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₄, SR₄, NR₄R₅, N(=O)₂, NR₄RO₅, ONR₄R₅, SOR₄,SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃,B(R₄)₂]alkyl; R₆ is selected from R₄, R₅, CN, COR₄, CO₂R₄, OR₄, SR₄,NR₄R₅, N(=O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅,SO₃NR₅, P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂; E′ and R′ or H′ and O′ is aC₂-C₈ saturated or unsaturated carbocyclic or heterocyclic ring systemfurther substituted by R₆, including epoxides and thioepoxides; O′connected to M′ (or N′) or Q′ (or P′); R′ connected to Q′60 (or P′) orS′ (or T′); S′ (or T′) connected to A′ (or B′); A′ (or B′) connected toC′ (or D′); E′ connected to C′ (or D′) or F′ (or G′); H′ connected toI′; I′ connected to J′; J′ connected to K′; K′ connected to L′; L′connected to M′ (or N′) are C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic ring systems further substitutedby R₆, (C=X)R₆ and X(C=X)R₆, including epoxides and thioepoxides; A′,B′and C′, D′and F′, G′and M′, N′and P′Q′and S′T′are =X where X isselected from sulfur, oxygen, nitrogen, NR4R₅, (C=X)R₆, X(CX)R₆, and=CR₇R₈; R₇ and R₈ are each independently selected from R₆, (C=X)R₆ andX(C=X)R₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A¹-T¹ are independently selected from hydrogen, R₉,R₁₀, R₁₁, F, Cl, Br, I, CN, OR₉, SR₉, NR₉R₁₀, N(=O)₂, NR₉OR₁₀, ONR₉R₁₀,SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃,Si(R₉)₃, B(R₉)₂, (C=X)R₁₁ or X(C=X)R₁₁, where X is selected fromsulfiur, oxygen and nitrogen; R₉ and R₁₀ are each independently selectedfrom C₁-C₂₀ alkyl (branched and straight chained), C₁-C₂₀ arylalkyl,C₃-C₈ cycloalkyl, C₆-CI₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle,C₂-C₁₀ alkenyl (branched and straight chained), C₂-C₁₀ alkynyl (branchedand straight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl,C₁-C₁₀ haloalkyl, dihaloalkyl, trialoalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₉,SR₉, NR₉R₁₀, N(=O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀,SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂]alkyl; R₁₁, isselected from R₉, R₁₀, CN, COR₉, CO₂R₉, OR₉, SR₉, NR₉R₁₀, N(=O)₂,NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀,P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂; B¹ and R¹, E¹ and Ö¹ and Ë¹ and M¹are selected from a C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₁, including epoxidesand thioepoxides; A¹ (or Ä¹ connected to Á¹ (or Ã¹) or T¹ (or S¹); B¹connected to Á¹ (or Ã¹) or C¹ (or D¹). E¹ connected to Ë¹ or C¹ (or D¹);Ë¹ connected to É¹ (or F¹); G¹ (or H¹) connected to É¹ (or F¹) or I¹ (orJ¹); K¹ (or L¹) connected to I¹ (or J¹) or M¹; M¹ connected to O¹ (orN¹); Ö¹ connected O¹ (or N¹) or P¹ (or Q¹); R¹ connected P¹ (or Q¹) orS¹ (or T¹) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₁,(C=X)R₁₁, and X(C=X)R₁₁, including epoxides and thioepoxides; A¹, Ä andÁ, Ã and C¹, D¹ and F¹, É and G¹, H¹ and I¹, J¹ and K¹, L¹ and N¹, O¹and P¹, Q¹ and S¹, T¹ are =X where X is selected from sulfur, oxygen,nitrogen, NR₉R₁₀, including (C=X)R₁₁, and X(C=X)R₁₁, and =CR₁₂R₁₃; R₁₂and R₁₃ are independently selected from R₁₁, (C=X)R₁₁, and X(C=X)R₁₁,

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen,sulfuir, phosphorus, silicon, boron, arsenic and selenium, wherein thering defined by said atoms is saturated or unsaturated, includingepoxides and thioepoxides; A²-X² are independently selected fromhydrogen, R₁₄, R₁₅, R₁₆, F, Cl, Br, I, CN, OR₁₄, SR₁₄, NR₁₄R₁₅, N(=O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₁₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄), (C=Y)R₁₆ orY(C=Y)R₁₆ where Y is selected from sulfur, oxygen and nitrogen; R₁₄ andR₁₅ are each independently selected from C₁-C₂₀ alkyl (branched and/orstraight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl,C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle C₂-C₁₀ alkenyl (branched and/orstraight chained), C₂-C₁₀ allkynyl (branched and/or straight chained),C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl,dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₄, SR₁₄, NR₁₄R₁₀ ,N(=O)₂, NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅,SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅, P(R₁₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂]alkyl;R₁₆ is selected from R₁₄, R₁₅, CN, COR₁₄, CO₂R₁₅, OR₁₄, SR₁₄, N₁₄R₁₅,N(=O)₂, NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, S₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂; E² and V², and H²and S², and I² and P² are C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₆, including epoxidesand thioepoxides; A² (or B²) connected to C² (or D²) or W² (or X²); E²connected to C² (or D²) or F² (or G²); H² connected to F² (or G² or I²;I² connected to J² (or K²); L² (or M²) connected to J² (or K²) or N² (orO²); R² (or Q² connected to P² or S²; V² connected to U² (or T²) or W²(or X²) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₆,(C=Y)R₁₆ and Y(C=Y)R₁₆, including epoxides and thioepoxides; A², B²; C²,D²; F², G²; J², K²; L², M²; N², O²; O², R²; U², T² and X², W² are =Ywhere Y is selected from sulfur, oxygen, nitrogen, NR₁₄R₁₅ and =CR₁₇R₁₈;R₁₇ and R₁₈ are independently selected from R₁₆, (C=Y)R₁₆ and Y(C=Y)R₁₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen,sulfuir, phosphorus, silicon, boron, arsenic and selenium, wherein thering defined by said atoms is saturated or unsaturated, includingepoxides and thioepoxides; A³-Z³ are independently selected fromhydrogen, R₁₉, R₂₀, R₂₁, F, Cl, Br, I, CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂,NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀,SO₃NR₁₉R₂₀, P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂, (C=Ø)R₂₁ orØ(C=Ø)R₂₁ where Ø is sulfur, oxygen and nitrogen; R₁₉ and R₂₀ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ alkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ allkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂,NR,₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀,SO₃NR₁₉R₂₀, P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂]alkyl; R₂₁ isselected from R₁₉, R₂₀, CN, COR₁₉, CO₂R₁₉, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂,NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀,SO₃NR₁₉R₂₀, P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂; D³ connected to X³is a C₂-C₈ saturated or unsaturated carbocyclic or heterocyclic ringsystem further substituted by R₂₁, including epoxides and thioepoxides;A³ (or Ä³) connected to B³ (or C³) or Z³ (or Y³); D³ connected to B³ (orC³) or E³ (or F³); G³ (or H³) connected to E³ (or F³) or I³ (or J³); L³(or K³) connected to I³ (or J³) or M³ (or N³); O³ (or Ö³) connected toN³ (or M³) or P³ (or Q³). S³ (or R³) connected to Q³ (or P³) or U³ (orT³). W³ (or V³) connected to U³ (or T³) or X³; X³ connected to Y³ (orZ³) are C₁-C₈ disubstituted (fused) saturated or unsaturated carbocyclicor heterocyclic ring systems further substituted by R₂₁, (C=Ø)R₂₁ and Ø(C=Ø)R₂₁, including epoxides and thioepoxides; A³, Ä³;B³,C³; E³,F³; G³,H³; I³, J³; K³, L³; M³,N³; O³, {umlaut over (0)}³; Q³,P³, R³, U³, T³,W³, V³, and Z³,Y³ are =Ø where Ø is selected from sulfur, oxygen,nitrogen, NR₁₉R₂₀, and =CR₂₂R₂₃; and R₂₂ and R₂₃ are selected from R₂₁,(C=Ø)R₂₁ and Ø (C=Ø)R₂₁; and which chemical agent or derivative orchemical analog is administered for a time and under conditionssufficient to ameliorate one or more symptoms associated with said,prostate cancer or related cancer or condition.
 2. A method according toclaim 1 wherein the chemical agent is represented. by the generalforrnula (VI):

wherein: R₂₄, R₂₅ and R₂₆ are independently selected from hydrogen, R₂₇,R₂₈, F, Cl, Br, I, CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, Nr₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(=O)(R₂₇)₃,Si(R₂₇)₃, B(R₂₇)₂, (C=X)R₂₉ or X(C=X)R₂₉ where X is selectedfrom sulfur, oxygen and nitrogen; R₂₇ and R₂₈ are each independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C14heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂]alkyl; R₂₉ is selected from R₂₇, R₂₈, CN,COR₂₇, CO₂R₂₇, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇,SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃, P(=O)(R₂₇)₃,Si(R₂₇)₃, B(R₂₇)₂.
 3. A method according to claim 2 wherein R₂₄ is H. 4.A method according to claim 2 wherein R₂₄ is OAcetyl.
 5. A methodaccording to claim 2 wherein R₂₄ is OH.
 6. A method according to claim 2wherein R₂₅ is OH.
 7. A method according to claim 2 wherein R₂₆ is OH.8. A method according to claim 1 wherein the plant is of the genusselected from Acalypha, Acidoton, Actinostemon, Adelia, Adenocline,Adenocrepis, Adenophaedra, Adisca, Agrostistachys, Alchornea,Alchorneopsis, Alcinaeanthus, Alcoceria, Aleurites, Amanoa, Andrachne,Angostyles, Anisophllum, Antidesmia, Aphora, Aporosa, Aporosella,Argythamnia, Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia,Beyeriopsis, Bischofia, Blachia, Blumeodondron, Bonania, Bradleia,Breynia, Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron,Celianella, Cephalocroton, Chaenotheca, Chaetocarpus, Chanaesyce,Cheilosa, Chiropetalum, Choriophyllum, Cicca, Chaoxylon, Cleidon,Cleistanthus, Cluytia, Cnesmone, Cnidoscolus, Coccoceras, Codiaeum,Coelodiscus, Conami, Conceveiba, Conceveibastrum, Conceveibum, Corythea,Croizatia, Croton, Crotonopsis, Crozophora, Cubanthus, Cunuria,Dactylostemon, Dalechampia, Dendrocousinsia, Diaspersus, Didymocistus,Dimorphocalyx, Discocarpus, Ditaxis, Dodecastingma, Drypetes, Dysopsis,Elateriospermum, Endadenium, Endospermum, Erismanthus, Erythrocarpus,Erythrochilus, Eumecanthus, Euphorbia, Euphorbiodendron, Excoecaria,Flueggea, Calearia, Garcia, Gavarretia, Gelonium, Giara, Givotia,Glochidion, Clochidionopsis, Glycydendron, Gymnanthes, Gymnosparia,Haematospermum, Hendecandra, Hevea, Hieronima, Hieronyma,Hippocrepandra, Homalanthus, Hymenocardia, Janipha, Jatropha,Julocroton, Lasiocroton, Leiocarpus, Leonardia, Lepidanthus,Leucocroton, Mabea, Macaranga, Mallotus, Manihot, Mappa, Maprounea,Melanthesa, Mercurialis, mettenia, Micrandra, Microdesmis, Microelus,Microstachy, Maocroton, Monadenium, Mozinnia, Neoscortechinia,Omalanthus, Omphalea, Ophellantha, Orbicularia, Ostodes, Oxydectes,Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilandthus, Pera,Peridium,Petalostigima, Phyllanthus, Picrodendro, Pierardia,Pilinophytum, Pimeleodendron, Piranhea, Platygyna, Plukenetia,Podocalyx, Poinsettia, Poraresia, Prosartema, Pseudanthus, Pycnocoma,Ouadrasia, Reverchonia, Richeria, Richeriella, Ricinella,Ricinocarpus,Rottlera, Sagotia, Sanwithia, Sapium, Savia, Sclerocroton, Sebastiana,Securinega, Senefeldera, Senefilderopsis, Serophyton, Siphonia,Spathiostemon, Spixia, Stillingia, Strophioblachia, Synadenium,Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanthera, Tithymalus,Trageia, Trewia, Trigonostemon, Tyria and Xylophylla.
 9. A methodaccording to claim 7 wherein the plant is of the genus Euphorbia.
 10. Amethod according to claim 8 wherein the species of Euphorbia is selectedfrom Euphorbia aaron-rossii, Euphorbia abbreviata, Euphorbia acuta,Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbia algomarginata,Euphorbia aliceae, Euphorbia alta, Euphorbia anacampseros, Euphorbiaandromedae, Euphorbia angusta, Euphorbia anthonyi, Euphorbiaantiguensis, Euphorbia apocynifolia, Euphorbia arabica, Euphorbiaariensis, Euphorbia arizonica, Euphorbia arkansana, Euphorbia arteagae,Euphorbia arundelana, Euphorbia astroites, Euphorbia atrococca,Euphorbia baselicis, Euphorbia batabanensis, Euphorbia bergeR ₁,Euphorbia bermudiana, Euphorbia bicolor, Euphorbia biformis, Euphorbiabifurcata, Euphorbia bilobata, Euphorbia biramensis, Euphorbiabiuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbiaboerhaavioides, Euphorbia boliviana, Euphorbia bracei, Euphorbiabrachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbiabrittonii, Euphorbia caesia, Euphorbia calcicola, Euphorbia campestris,Euphorbia candelabrum, Euphorbia capitellata, Euphorbia carmenensis,Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides,Euphorbia chalicophila, Euphorbia chamaerrhodos, Euphorbia chamaesula,Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens,Euphorbia clarionensis, Euphorbia colimae, Euphorbia colorata, Euphorbiacommuntata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbiacorallifera, Euphorbia creberrima, Euphorbia crenulata, Euphorbiacubensis, Euphorbia cuspidata, Euphorbia cymbiformis, Euphorbiadarlingtonii, Euphorbia defoliata, Euphorbia degeneR₁, Euphorbiadeltoidea, Euphorbia dentata, Euphorbia depressa Euphorbia dictyosperma,Euphorbia dictyosperma, Euphorbia dioeca, Euphorbia discoidalis,Euphorbia dorsiventralis, Euphorbia drumondii, Euphorbia duclouxii,Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbiaeglandulosa, Euphorbia elata, Euphorbia enzalla, Euphorbia eriogonoides,Euphorbia eriophylla, Euphorbia esculaeformis, Euphorbia espirituenisis,Euphorbia esula, Euphorbia excisa, Euphorbia exclusa, Euphorbiaexstipitata, Euphorbia exstipulata, Euphorbia fendleR₁, Euphorbiafilicaulis, Euphorbia filiformis, Euphorbia florida, Euphorbiafruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbiagerardiania, Euphorbia geyeR₁, Euphorbia glyptosperma, Euphorbiagorgonis, Euphorbia gracilior, Euphorbia gracillima, Euphorbia gradyi,Euphorbia graminea, Euphorbia graminiea Euphorbia grisea, Euphorbiaguadalajarana, Euphorbia guanarensis, Euphorbia gymnadenia, Euphorbiahaematantha, Euphorbia hedyotoides, Euphorbia heldrichii, Euphorbiahelenae, Euphorbia helleR₁, Euphorbia helwigii, Euphorbia henricksonii,Euphorbia heterophylla, Euphorbia hexagona, Euphorbia hexagonoides,Euphorbia hinkleyorum, Euphorbia hintonii, Euphorbia hirtula, Euphorbiahirta, Euphorbia hooveR₁, Euphorbia humistrata, Euphorbia hypericifolia,Euphorbia inundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbiajejuna, Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii,Euphorbia lasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbialatericolor, Euphorbia laxiflora Euphorbia lecheoides, Euphorbialedienii, Euphorbia leucophylla, Euphorbia lineata, Euphorbialinguiformis, Euphorbia longecornuta, Euphorbia longepetiolata,Euphorbia longeramosa, Euphorbia longinsulicola, Euphorbia longipila,Euphorbia lupulina, Euphorbia lurida, Euphorbia lycioides, Euphorbiamacropodoides, macvaughiana, Euphorbia manca, Euphorbia mandoniania,Euphorbia mangleti, Euphorbia mango, Euphorbia marylandica, Euphorbiamayana, Euphorbia melanadenia, Euphorbia melanocarpa, Euphorbiameridensis, Euphorbia mertonii, Euphorbia mexiae, Euphorbiamicrocephala, Euphorbia microclada, Euphorbia micromera, Euphorbiamisella, Euphorbia missurica, Euphorbia montana, Euphorbia montereyana,Euphorbia multicaulis, Euphorbia multiformis, Euphorbia multinodis,Euphorbia multiseta, Euphorbia muscicola, Euphorbia neomexicana,Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia oaxacana,Euphorbia occidentalis, Euphorbia odontodemia, Euphorbia olivacea,Euphorbia olowaluana, Euphorbia opthalmica, Euphorbia ovata, Euphorbiapachypoda, Euphorbia pachyrhiza, Euphorbia padifolia, Euphorbia palmeR₁,Euphorbia paludicola, Euphorbia paralias, Euphorbia parciflora,Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana, Euphorbiapediculifera, Euphorbia peplidion, Euphorbia peploides, Euphorbiapeplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbia petaloidea,Euphorbia petaloidea, Euphorbia petrina, Euphorbia picachensis,Euphorbia pilosula, Euphorbia pilulifera, Euphorbia pinariona, Euphorbiapinetorum, Euphorbia pioniosperma, Euphorbia platysperma, Euphorbiaplicata, Euphorbia poeppigii, Euphorbia poliosperma, Euphorbiapolycarpa, Euphorbia polycnemioides, Euphorbia polyphylla, Euphorbiaportoricensis, Euphorbia portulacoides Euphorbia portulana, Euphorbiapreslii, Euphorbia prostrata, Euphorbia pteroneura, Euphorbiapycnanthema, Euphorbia ramosa, Euphorbia rapulum, Euphorbia remyi,Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis,Euphorbia robusta, Euphorbia romosa, Euphorbia rubida, Euphorbiarubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbiasaxatilis M. Bieb, Euphorbia schizoloba, Euphorbia sclerocyathium,Euphorbia scopulorum, Euphorbia senilis, Euphorbia serpyllifolia,Euphorbia serrula, Euphorbia setiloba Engelm, Euphorbia sonorae,Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerosperma,Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea,Euphorbia stellata, Euphorbia submammilaris, Euphorbia subpeltata,Euphorbia subpubens, Euphorbia subrenforme, Euphorbia subtrifoliata,Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides,Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli,Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii,Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor,Euphorbia troyana, Euphorbia tuerckheimii, Euphorbia turczaninowii,Euphorbia umbellulata, Euphorbia undulata, Euphorbia vermiformis,Euphorbia versicolor, Euphorbia villifera, Euphorbia violacea, Euphorbiawhitei, Euphorbia xanti Engelm, Euphorbia xylopoda Greenm., Euphorbiayayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica andEuphorbia zinniiflora.
 11. A method according to claim 9 wherein thespecies of Euphorbia is Euphorbia peplus.
 12. A method according toclaim 1 wherein the cancer is prostate cancer.
 13. A method according toany one of claims 1 to 12 wherein the chemical agent is coupled to atargeting agent.
 14. A method according to claim 13 wherein thetargeting agent is a bone-seeking agent.
 15. A method according to claim14 wherein the bone-seeking agent is bisphosphonate.
 16. A methodaccording to claim 15 wherein the bisphosphonate is methylenedisphosphonate.
 17. A method according to claim 13 wherein the targetingagent is an antibody to a prostate-specific tunmor marker.
 18. A methodaccording to claim 17 wherein the marker is prostate-specific antigen(PSA), prostate-specific membrane antigen (PMSA) or PSA receptor.
 19. Amethod for the treatment or prophylaxis of prostate cancer or a relatedcancer or condition in a subject, said method comprising theadministration to said subject of a symptom-ameliorating effectiveamount of a chemical agent obtainable from Euphorbia peplus or aderivative or chemical analog thereof which chemical agent is aditerpene selected from compounds of the ingenane, pepluane andjatrophane faiilies and X which chemical agent or derivative or chemicalanalog is represented by any one of the general formulae (I)-(V):

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen,sulfiur, phosphorus, silicon, boron, arsenic and selenium, wherein thering defmed by said atoms is saturated or unsaturated, includingepoxides and thioepoxides; A-T are independently selected fiom hydrogen,R₁, R₂, R₃, F, Cl, Br, I, CN, OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂,SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃,Si(R₁)₃, B(R₁)₂, (C=X)R₃ or X(C=X)R₃ where X is selected from sulfur,oxygen and nitrogen; R₁ and R₂ are each independently selected fromC₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀alkenyl (branched and/or straight chained), C₂-C₁₀ alkynyl (branchedand/or straight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ allcoxyalkyl,C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN,OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂,SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂]alkyl; R₃ isselected from R₁, R₂, CN, COR₁, CO₂R₁, OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂,ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃,P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂; A connected to B (or C), D (or E), R (orQ), P (or O) or S (or T) is a selection of C₁-C₈ disubstituted (fused)saturated or unsaturated carbocyclic or heterocyclic rings furthersubstituted by R₃, (C=X)R₃ and X(C=X)R₃, including epoxides andthioepoxides; J connected to I (or H), G (or F), K (or L), M (or N) or S(or T) is a selection of C₁-C₈ disubstituted (fused) saturated andunsaturated carbocyclic or heterocyclic rings further substituted by R₃,(C=X)R₃ and X(C=X)R₃, including epoxides and thioepoxides; D (or E)connected to B (or C) or G (or F); I (or H) connected to G (or F); P (orO) connected to R (or Q) or M (or N); K (or L) connected to N (or M) isa selection of C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic rings substituted by R₃, (C=X)R₃ andX(C=X)R₃, including epoxides and thioepoxides; B and C, D and E, R andQ, P and O, I and H, G and F, K and L M and N or S and T are =X where Xis selected from sulfur, oxygen, nitrogen, NR₁R₂, and =CriR₂

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A′-T′ are independently selected from hydrogen, R₄,R₅, R₆, F, Cl, Br, I, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅, CONR₄R₅, N(=O)₂,NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃,P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂, (C=X)R₆ or X(C=X)R₆ where X is selectedfrom sulfur, oxygen and nitrogen; R₄ and R₅ are each, independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₄, SR₄, NR₄R₅, N(=O)₂, NR₄RO₅, ONR₄R₅, SOR₄,SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃,B(R₄)₂]alkyl; R₆ is selected from R₄, R₅, CN, COR₄, CO₂R₄, OR₄, SR₄,NR₄R₅, N(=O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅,SO₃NR₅, P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂; E′ and R′ or H′ and O′ is aC₂-C₈ saturated or unsaturated carbocyclic or heterocyclic ring systemfurther substituted by R₆, including epoxides and thioepoxides; O′connected to M′ (or N′) or Q′ (or P′); R′ connected to Q′60 (or P′) orS′ (or T′); S′ (or T′) connected to A′ (or B′); A′ (or B′) connected toC′ (or D′); E′ connected to C′ (or D′) or F′ (or G′); H′ connected toI′; I′ connected to J′; J′ connected to K′; K′ connected to L′; L′connected to M′ (or N′) are C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic ring systems further substitutedby R₆, (C=X)R₆ and X(C=X)R₆, including epoxides and thioepoxides; A′,B′and C′, D′and F′, G′and M′, N′and P′Q′and S′T′are =X where X isselected from sulfur, oxygen, nitrogen, NR4R₅, (C=X)R₆, X(CX)R₆, and=CR₇R₈; R₇ and R₈ are each independently selected from R₆, (C=X)R₆ andX(C=X)R₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A¹-T¹ are independently selected from hydrogen, R₉,R₁₀, R₁₁, F, Cl, Br, I, CN, OR₉, SR₉, NR₉R₁₀, N(=O)₂, NR₉OR₁₀, ONR₉R₁₀,SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃,Si(R₉)₃, B(R₉)₂, (C=X)R₁₁ or X(C=X)R₁₁, where X is selected fromsulfiur, oxygen and nitrogen; R₉ and R₁₀ are each independently selectedfrom C₁-C₂₀ alkyl (branched and straight chained), C₁-C₂₀ arylalkyl,C₃-C₈ cycloalkyl, C₆-CI₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle,C₂-C₁₀ alkenyl (branched and straight chained), C₂-C₁₀ alkynyl (branchedand straight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl,C₁-C₁₀ haloalkyl, dihaloalkyl, trialoalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₉,SR₉, NR₉R₁₀, N(=O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀,SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂]alkyl; R₁₁, isselected from R₉, R₁₀, CN, COR₉, CO₂R₉, OR₉, SR₉, NR₉R₁₀, N(=O)₂,NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀,P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂; B¹ and R¹, E¹ and Ö¹ and Ë¹ and M¹are selected from a C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₁, including epoxidesand thioepoxides; A¹ (or Ä¹ connected to Á¹ (or Ã¹) or T¹ (or S¹); B¹connected to Á¹ (or Ã¹) or C¹ (or D¹). E¹ connected to Ë¹ or C¹ (or D¹);Ë¹ connected to É¹ (or F¹); G¹ (or H¹) connected to É¹ (or F¹) or I¹ (orJ¹); K¹ (or L¹) connected to I¹ (or J¹) or M¹; M¹ connected to O¹ (orN¹); Ö¹ connected O¹ (or N¹) or P¹ (or Q¹); R¹ connected P¹ (or Q¹) orS¹ (or T¹) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₁,(C=X)R₁₁, and X(C=X)R₁₁, including epoxides and thioepoxides; A¹, Ä andÁ, Ã and C¹, D¹ and F¹, É and G¹, H¹ and I¹, J¹ and K¹, L¹ and N¹, O¹and P¹, Q¹ and S¹, T¹ are =X where X is selected from sulfur, oxygen,nitrogen, NR₉R₁₀, including (C=X)R₁₁, and X(C=X)R₁₁, and =CR₁₂R₁₃; R₁₂and R₁₃ are independently selected from R₁₁, (C=X)R₁₁, and X(C=X)R₁₁,

wherein: n is 0-10 atoms selected fiom carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A²-X² are independently selected from hydrogen, R₁₄,R₁₅, R₁₆, F, Cl, Br, I, CN, OR₁₄, SR₁₄, NR₁₄R₁₅, N(=O)₂, NR₁₄OR₁₅,ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅,P(R₁₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄), (C=Y)R₁₆ or Y(C=Y)R₁₆ where Y isselected from sulfur, oxygen and nitrogen; R₁₄ and R₁₅ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ allkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₄, SR₁₄, NR₁₄R₁₀ , N(=O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₁₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂]alkyl; R₁₆ isselected from R₁₄, R₁₅, CN, COR₁₄, CO₂R₁₅, OR₁₄, SR₁₄, N₁₄R₁₅, N(=O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, S₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂; E² and V², and H²and S², and I² and P² are C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₆, including epoxidesand thioepoxides; A² (or B²) connected to C² (or D²) or W² (or X²); E²connected to C² (or D²) or F² (or G²); H² connected to F² (or G² or I²;I² connected to J² (or K²); L² (or M²) connected to J² (or K²) or N² (orO²); R² (or Q² connected to P² or S²; V² connected to U² (or T²) or W²(or X²) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₆,(C=Y)R₁₆ and Y(C=Y)R₁₆, including epoxides and thioepoxides; A², B²; C²,D²; F², G²; J², K²; L², M²; N², O²; O², R²; U², T² and X², W² are =Ywhere Y is selected from sulfur, oxygen, nitrogen, NR₁₄R₁₅ and =CR₁₇R₁₈;R₁₇ and R₁₈ are independently selected from R₁₆, (C=Y)R₁₆ and Y(C=Y)R₁₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A³-Z³ are independently selected from hydrogen, R₁₉,R₂₀, R₂₁, F, Cl, Br, I, CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂, NR₁₉OR₂₀,ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀,P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂, (C=Ø)R₂₁ or Ø (C=Ø)R₂₁ where Øis sulfur, oxygen and nitrogen; R₁₉ and R₂₀ are each independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ allkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂, NR,₁₉OR₂₀,ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀,P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂]alkyl; R₂₁ is selected from R₁₉,R₂₀, CN, COR₁₉, CO₂R₁₉, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀,SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃,P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂; D³ connected to X³ is a C₂-C₈ saturatedor unsaturated carbocyclic or heterocyclic ring system furthersubstituted by R₂₁, including epoxides and thioepoxides; A³ (or Ä³)connected to B³ (or C³) or Z³ (or Y³); D³ connected to B³ (or C³) or E³(or F³); G³ (or H³) connected to E³ (or F³) or I³ (or J³); L³ (or K³)connected to I³ (or J³) or M³ (or N³); O³ (or Ö³) connected to N³ (orM³) or P³ (or Q³). S³ (or R³) connected to Q³ (or P³) or U³ (or T³). W³(or V³) connected to U³ (or T³) or X³; X³ connected to Y³ (or Z³) areC₁-C₈ disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic ring systems further substituted by R₂₁, (C=Ø)R₂₁ and Ø(C=Ø)R₂₁, including epoxides and thioepoxides; A³, A³;B³,C³; E³,F³; G³,H³; I³, J³; K³, L³; M³,N³; O³, {umlaut over (0)}³; Q³,P³, R³, U³, T³,W³, V³, and Z³,Y³ are =Ø where Ø is selected from sulfur, oxygen,nitrogen, NR₁₉R₂₀, and =CR₂₂R₂₃; and R₂₂ and R₂₃ are selected from R₂₁,(C=Ø)R₂₁ and Ø (C=Ø)R₂₁; and which chemical agent or derivative orchemical analogis administered for a time and under conditionssufficient to ameliorate one or more symptoms associated with saidprostate cancer or related cancer or condition.
 20. A method accordingto claim 19 wherein the chemical agent is represented by the generalformula (VI):

wherein: R₂₄, R₂₅ and R₂₆ are independently selected from hydrogen, R₂₇,R₂₈, F, Cl, Br, I, CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, Nr₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(=O)(R₂₇)₃,Si(R₂₇)₃, B(R₂₇)₂, (C=X)R₂₉ or X(C=X)R₂₉ where X is selectedfrom sulfur, oxygen and nitrogen; R₂₇ and R₂₈ are each independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C14heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂]alkyl; R₂₉ is selected from R₂₇, R₂₈, CN,COR₂₇, CO₂R₂₇, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇,SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃, P(=O)(R₂₇)₃,Si(R₂₇)₃, B(R₂₇)₂.
 21. A method according to claim 20 wherein R₂₄ is H.22. A method according to claim 20 wherein R₂₄ is OAcetyl.
 23. A methodaccording to claim 20 wherein R₂₄ is OH.
 24. A method according to claim20 wherein R₂₅ is OH.
 25. A method according to claim 20 wherein R₂₆ isOH.
 26. A method according to claim 19 wherein the cancer is prostatecancer.
 27. A method according to any one of claims 19 to 26 wherein thechemical agent is coupled to a targeting agent.
 28. A method accordingto claim 27 wherein the targeting agent is a bone-seeking agent.
 29. Amethod according to claim 28 wherein the bone-seelking agent isbisphosphonate.
 30. A method according to claim 29 wherein thebisphosphonate is methylene disphosphonate.
 31. A method according toclaim 27 wherein the targeting agent is an antibody to aprostate-specific tumor marker.
 32. A method according to claim 31wherein the marker is prostate-specific antigen (PSA), prostate-specificmembrane antigen (PMSA) or PSA receptor.
 33. A method for theimmunopotentiation of a subject in the treatment or prophylaxis ofprostate cancer or a related condition, said method comprising theadministration to said subject of a symptom-ameliorating effectiveamount of a chemical agent obtainable from a plant of the Euphorbiaceaefanily or a derivative or chemical analog thereof which chenical agentis a diterpene selected from compounds of the ingenane, pepluane andjatrophane families and which chemical agent or derivative or chemicalanalog is represented by any one of the general formulae (I)-(V):-

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A-T are independently selected from hydrogen, R₁, R₂,R₃, F, Cl, Br, I, CN, OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁,SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃,B R1)2, (C=X)R₃ or X(C=X)R₃ where X is selected from sulfuir, oxygen andnitrogen; R₁ and R₂ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched andlorstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloallkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁, SR₁,NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂,SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃, B(R₁)₂]alkyl; R₃ is selected fromR₁, R₂, CN, COR₁, CO₂R₁, OR₁, SR₁, NR₁R₂, N(=O)₂, NR₁OR₂, ONR₁R₂, SOR₁,SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(=O)(R₁)₃, Si(R₁)₃,B(R₁)₂; A connected to B (or C), D (or E), R (or Q), P (or O) or S (orT) is a selection of C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic rings further substituted by R₃,(C=X)R₃ and X(C=X)R₃, including epoxides and thioepoxides; J connectedto I (or H), G (or F), K (or L), M (or N) or S (or T) is a selection ofC₁-C₈ disubstituted (fused) saturated and unsaturated carbocyclic orheterocyclic rings further substituted by R₃, (C=X)R₃ and X(C=X)R₃,including epoxides and thioepoxides; D (or E) connected to B (or C) or G(or F); I (or H) connected to G (or F); P (or O) connected to R (or Q)or M (or N); K (or L) connected to N (or M) is a selection of C₁-C₈disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic rings substituted by R₃, (C=X)R₃ and X(C=X)R₃, includingepoxides and thioepoxides; B and C, D and E, R and Q, P and O, I and H,G and F, K and L, M and N or S and T are =X where X is selected fromsulfur, oxygen, nitrogen, NR₁R₂, and =Cr₁R₂

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfiu,phosphorus, silicon, boron, arsenlic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A′-T′ are independently selected from hydrogen, R₄,R₅, R₆, F, Cl, Br, I, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅, CONR₄R₅, N(=O)₂,NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃,P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂, (C=X)R₆ or X(C=X)R₆ where X is selectedfrom sulfur, oxygen and nitrogen; R₄ and R₅ are each, independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₄, SR₄, NR₄R₅, N(=O)₂, NR₄RO₅, ONR₄R₅, SOR₄,SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃,B(R₄)₂]alkyl; R₆ is selected from R₄, R₅, CN, COR₄, CO₂R₄, OR₄, SR₄,NR₄R₅, N(=O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅,SO₃NR₅, P(R₄)₃, P(=O)(R₄)₃, Si(R₄)₃, B(R₄)₂; E′ and R′ or H′ and O′ is aC₂-C₈ saturated or unsaturated carbocyclic or heterocyclic ring systemfurther substituted by R₆, including epoxides and thioepoxides; O′connected to M′ (or N′) or Q′ (or P′); R′ connected to Q′60 (or P′) orS′ (or T′); S′ (or T′) connected to A′ (or B′); A′ (or B′) connected toC′ (or D′); E′ connected to C′ (or D′) or F′ (or G′); H′ connected toI′; I′ connected to J′; J′ connected to K′; K′ connected to L′; L′connected to M′ (or N′) are C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic ring systems further substitutedby R₆, (C=X)R₆ and X(C=X)R₆, including epoxides and thioepoxides; A′,B′and C′, D′and F′, G′and M′, N′and P′Q′and S′T′are =X where X isselected from sulfur, oxygen, nitrogen, NR4R₅, (C=X)R₆, X(CX)R₆, and=CR₇R₈; R₇ and R₈ are each independently selected from R₆, (C=X)R₆ andX(C=X)R₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A¹-T¹ are independently selected from hydrogen, R₉,R₁₀, R₁₁, F, Cl, Br, I, CN, OR₉, SR₉, NR₉R₁₀, N(=O)₂, NR₉OR₁₀, ONR₉R₁₀,SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃,Si(R₉)₃, B(R₉)₂, (C=X)R₁₁ or X(C=X)R₁₁, where X is selected fromsulfiur, oxygen and nitrogen; R₉ and R₁₀ are each independently selectedfrom C₁-C₂₀ alkyl (branched and straight chained), C₁-C₂₀ arylalkyl,C₃-C₈ cycloalkyl, C₆-CI₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle,C₂-C₁₀ alkenyl (branched and straight chained), C₂-C₁₀ alkynyl (branchedand straight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl,C₁-C₁₀ haloalkyl, dihaloalkyl, trialoalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₉,SR₉, NR₉R₁₀, N(=O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀,SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂]alkyl; R₁₁, isselected from R₉, R₁₀, CN, COR₉, CO₂R₉, OR₉, SR₉, NR₉R₁₀, N(=O)₂,NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀,P(R₉)₃, P(=O)(R₉)₃, Si(R₉)₃, B(R₉)₂; B¹ and R¹, E¹ and Ö¹ and Ë¹ and M¹are selected from a C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₁, including epoxidesand thioepoxides; A¹ (or Ä¹ connected to Á¹ (or Ã¹) or T¹ (or S¹); B¹connected to Á¹ (or Ã¹) or C¹ (or D¹). E¹ connected to Ë¹ or C¹ (or D¹);Ë¹ connected to É¹ (or F¹); G¹ (or H¹) connected to É¹ (or F¹) or I¹ (orJ¹); K¹ (or L¹) connected to I¹ (or J¹) or M¹; M¹ connected to O¹ (orN¹); Ö¹ connected O¹ (or N¹) or P¹ (or Q¹); R¹ connected P¹ (or Q¹) orS¹ (or T¹) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₁,(C=X)R₁₁, and X(C=X)R₁₁, including epoxides and thioepoxides; A¹, Ä andÁ, Ã and C¹, D¹ and F¹, É and G¹, H¹ and I¹, J¹ and K¹, L¹ and N¹, O¹and P¹, Q¹ and S¹, T¹ are =X where X is selected from sulfur, oxygen,nitrogen, NR₉R₁₀, including (C=X)R₁₁, and X(C=X)R₁₁, and =CR₁₂R₁₃; R₁₂and R₁₃ are independently selected from R₁₁, (C=X)R₁₁, and X(C=X)R₁₁,

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A²-X² are independently selected from hydrogen, R₁₄,R₁₅, R₁₆, F, Cl, Br, I, CN, OR₁₄, SR₁₄, NR₁₄R₁₅, N(=O)₂, NR₁₄OR₁₅,ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅,P(R₁₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄), (C=Y)R₁₆ or Y(C=Y)R₁₆ where Y isselected from sulfur, oxygen and nitrogen; R₁₄ and R₁₅ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ allkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₄, SR₁₄, NR₁₄R₁₀ , N(=O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₁₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂]alkyl; R₁₆ isselected from R₁₄, R₁₅, CN, COR₁₄, CO₂R₁₅, OR₁₄, SR₁₄, N₁₄R₁₅, N(=O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, S₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₄)₃, P(=O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂; E² and V², and H²and S², and I² and P² are C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₆, including epoxidesand thioepoxides; A² (or B²) connected to C² (or D²) or W² (or X²); E²connected to C² (or D²) or F² (or G²); H² connected to F² (or G² or I²;I² connected to J² (or K²); L² (or M²) connected to J² (or K²) or N² (orO²); R² (or Q² connected to P² or S²; V² connected to U² (or T²) or W²(or X²) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₆,(C=Y)R₁₆ and Y(C=Y)R₁₆, including epoxides and thioepoxides; A², B²; C²,D²; F², G²; J², K²; L², M²; N², O²; O², R²; U², T² and X², W² are =Ywhere Y is selected from sulfur, oxygen, nitrogen, NR₁₄R₁₅ and =CR₁₇R₁₈;R₁₇ and R₁₈ are independently selected from R₁₆, (C=Y)R₁₆ and Y(C=Y)R₁₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A³-Z³ are independently selected from hydrogen, R₁₉,R₂₀, R₂₁, F, Cl, Br, I, CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂, NR₁₉OR₂₀,ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀,P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂, (C=Ø)R₂₁ or Ø (C=Ø)R₂₁ where Øis sulfur, oxygen and nitrogen; R₁₉ and R₂₀ are each independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ allkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂, NR,₁₉OR₂₀,ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀,P(R₁₉)₃, P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂]alkyl; R₂₁ is selected from R₁₉,R₂₀, CN, COR₁₉, CO₂R₁₉, OR₁₉, SR₁₉, NR₁₉R₂₀, N(=O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀,SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃,P(=O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂; D³ connected to X³ is a C₂-C₈ saturatedor unsaturated carbocyclic or heterocyclic ring system furthersubstituted by R₂₁, including epoxides and thioepoxides; A³ (or Ä³)connected to B³ (or C³) or Z³ (or Y³); D³ connected to B³ (or C³) or E³(or F³); G³ (or H³) connected to E³ (or F³) or I³ (or J³); L³ (or K³)connected to I³ (or J³) or M³ (or N³); O³ (or Ö³) connected to N³ (orM³) or P³ (or Q³). S³ (or R³) connected to Q³ (or P³) or U³ (or T³). W³(or V³) connected to U³ (or T³) or X³; X³ connected to Y³ (or Z³) areC₁-C₈ disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic ring systems further substituted by R₂₁, (C=Ø)R₂₁ and Ø(C=Ø)R₂₁, including epoxides and thioepoxides; A³, A³;B³,C³; E³,F³; G³,H³; I³, J³; K³, L³; M³,N³; O³, {umlaut over (0)}³; Q³,P³, R³, U³, T³,W³, V³, and Z³,Y³ are =Ø where Ø is selected from sulfur, oxygen,nitrogen, NR₁₉R₂₀, and =CR₂₂R₂₃; and R₂₂ and R₂₃ are selected from R₂₁,(C=Ø)R₂₁ and Ø (C=Ø)R₂₁; and which chemical agent or derivative orchemical analogis administered for a time and under conditionssufficient to potentiate the immune system or components therein.
 34. Amethod according to claim 33 wherein the chemical agent is representedby the general formula (VI):

wherein: R₂₄, R₂₅ and R₂₆ are independently selected from hydrogen, R₂₇,R₂₈, F, Cl, Br, I, CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, Nr₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(=O)(R₂₇)₃,Si(R₂₇)₃, B(R₂₇)₂, (C=X)R₂₉ or X(C=X)R₂₉ where X is selectedfrom sulfur, oxygen and nitrogen; R₂₇ and R₂₈ are each independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C14heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂]alkyl; R₂₉ is selected from R₂₇, R₂₈, CN,COR₂₇, CO₂R₂₇, OR₂₇, SR₂₇, NR₂₇R₂₈, N(=O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇,SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃, P(=O)(R₂₇)₃,Si(R₂₇)₃, B(R₂₇)₂.
 35. A method according to claim 33 wherein R₂₄ is H.36. A method according to claim 33 wherein R₂₄ is OAcetyl.
 37. A methodaccording to claim 33 wherein R₂₄ is OH.
 38. A method according to claim33 wherein R₂₅ is OH.
 39. A method according to claim 33 wherein R₂₆ isOH.
 40. A method according to claim 33 wherein the plant is of the genusselected from Acalypha, Acidoton, Actinostemon, Adelia, Adenocline,Adenocrepis, Adenophaedra, Adisca, Agrostistachys, Alchornea,Alchorneopsis, Alcinaeanthus, Alcoceria, Aleurites, Amanoa, Andrachne,Angostyles, Anisophllum, Antidesmia, Aphora, Aporosa, Aporosella,Argythamnia, Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia,Beyeriopsis, Bischofia, Blachia, Blumeodondron, Bonania, Bradleia,Breynia, Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron,Celianella, Cephalocroton, Chaenotheca, Chaetocarpus, Chanaesyce,Cheilosa, Chiropetalum, Choriophyllum, Cicca, Chaoxylon, Cleidon,Cleistanthus, Cluytia, Cnesmone, Cnidoscolus, Coccoceras, Codiaeum,Coelodiscus, Conami, Conceveiba, Conceveibastrum, Conceveibum, Corythea,Croizatia, Croton, Crotonopsis, Crozophora, Cubanthus, Cunuria,Dactylostemon, Dalechampia, Dendrocousinsia, Diaspersus, Didymocistus,Dimorphocalyx, Discocarpus, Ditaxis, Dodecastingma, Drypetes, Dysopsis,Elateriospermum, Endadenium, Endospermum, Erismanthus, Erythrocarpus,Erythrochilus, Eumecanthus, Euphorbia, Euphorbiodendron, Excoecaria,Flueggea, Calearia, Garcia, Gavarretia, Gelonium, Giara, Givotia,Glochidion, Clochidionopsis, Glycydendron, Gymnanthes, Gymnosparia,Haematospermum, Hendecandra, Hevea, Hieronima, Hieronyma,Hippocrepandra, Homalanthus, Hymenocardia, Janipha, Jatropha,Julocroton, Lasiocroton, Leiocarpus, Leonardia, Lepidanthus,Leucocroton, Mabea, Macaranga, Mallotus, Manihot, Mappa, Maprounea,Melanthesa, Mercurialis, mettenia, Micrandra, Microdesmis, Microelus,Microstachy, Maocroton, Monadenium, Mozinnia, Neoscortechinia,Omalanthus, Omphalea, Ophellantha, Orbicularia, Ostodes, Oxydectes,Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilandthus, Pera,Peridium,Petalostigima, Phyllanthus, Picrodendro, Pierardia,Pilinophytum, Pimeleodendron, Piranhea, Platygyna, Plukenetia,Podocalyx, Poinsettia, Poraresia, Prosartema, Pseudanthus, Pycnocoma,Ouadrasia, Reverchonia, Richeria, Richeriella, Ricinella,Ricinocarpus,Rottlera, Sagotia, Sanwithia, Sapium, Savia, Sclerocroton, Sebastiana,Securinega, Senefeldera, Senefilderopsis, Serophyton, Siphonia,Spathiostemon, Spixia, Stillingia, Strophioblachia, Synadenium,Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanthera, Tithymalus,Trageia, Trewia, Trigonostemon, Tyria and Xylophylla.
 41. A methodaccording to claim 40 wherein the plant is of the genus Euphorbia.
 42. Amethod according to claim 41 wherein the species of Euphorbia isselected from Euphorbiz aaron-rossii, Euphorbia abbreviata, Euphorbiaacuta, Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbiaalgomarginata, Euphorbia aliceae, Euphorbia alta, Euphorbiaanacampseros, Euphorbia andromedae, Euphorbia angusta, Euphorbiaanthonyi, Euphorbia antiguensis, Euphorbia apocynifolia, Euphorbiaarabica, Euphorbia ariensis, Euphorbia arizonica, Euphorbia arkansana,Euphorbia arteagae, Euphorbia arundelana, Euphorbia astroites, Euphorbiaatrococca, Euphorbia baselicis, Euphorbia batabanensis, Euphorbia bergeR₁, Euphorbia bermudiana, Euphorbia bicolor, Euphorbia biformis,Euphorbia bifurcata, Euphorbia bilobata, Euphorbia biramensis, Euphorbiabiuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbiaboerhaavioides, Euphorbia boliviana, Euphorbia bracei, Euphorbiabrachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbiabrittonii, Euphorbia caesia, Euphorbia calcicola, Euphorbia campestris,Euphorbia candelabrum, Euphorbia capitellata, Euphorbia carmenensis,Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides,Euphorbia chalicophila, Euphorbia chamaerrhodos, Euphorbia chamaesula,Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens,Euphorbia clarionensis, Euphorbia colimae, Euphorbia colorata, Euphorbiacommuntata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbiacorallifera, Euphorbia creberrima, Euphorbia crenulata, Euphorbiacubensis, Euphorbia cuspidata, Euphorbia cymbiformis, Euphorbiadarlingtonii, Euphorbia defoliata, Euphorbia degeneR₁, Euphorbiadeltoidea, Euphorbia dentata, Euphorbia depressa Euphorbia dictyosperma,Euphorbia dictyosperma, Euphorbia dioeca, Euphorbia discoidalis,Euphorbia dorsiventralis, Euphorbia drumondii, Euphorbia duclouxii,Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbiaeglandulosa, Euphorbia elata, Euphorbia enzalla, Euphorbia eriogonoides,Euphorbia eriophylla, Euphorbia esculaeformis, Euphorbia espirituenisis,Euphorbia esula, Euphorbia excisa, Euphorbia exclusa, Euphorbiaexstipitata, Euphorbia exstipulata, Euphorbia fendleri, Euphorbiafilicaulis, Euphorbia filiformis, Euphorbia florida, Euphorbiafruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbiagerardiania, Euphorbia geyeri, Euphorbia glyptosperma, Euphorbiagorgonis, Euphorbia gracilior, Euphorbia gracillima, Euphorbia gradyi,Euphorbia graminea, Euphorbia graminiea Euphorbia grisea, Euphorbiaguadalajarana, Euphorbia guanarensis, Euphorbia gymnadenia, Euphorbiahaematantha, Euphorbia hedyotoides, Euphorbia heldrichii, Euphorbiahelenae, Euphorbia helleri, Euphorbia helwigii, Euphorbia henricksonii,Euphorbia heterophylla, Euphorbia hexagona, Euphorbia hexagonoides,Euphorbia hinkleyorum, Euphorbia hintonii, Euphorbia hirtula, Euphorbiahirta, Euphorbia hooveR₁, Euphorbia humistrata, Euphorbia hypericifolia,Euphorbia inundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbiajejuna, Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii,Euphorbia lasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbialatericolor, Euphorbia laxiflora Euphorbia lecheoides, Euphorbialedienii, Euphorbia leucophylla, Euphorbia lineata, Euphorbialinguiformis, Euphorbia longecornuta, Euphorbia longepetiolata,Euphorbia longeramosa, Euphorbia longinsulicola, Euphorbia longipila,Euphorbia lupulina, Euphorbia lurida, Euphorbia lycioides, Euphorbiamacropodoides, macvaughiana, Euphorbia manca, Euphorbia mandoniania,Euphorbia mangleti, Euphorbia mango, Euphorbia marylandica, Euphorbiamayana, Euphorbia melanadenia, Euphorbia melanocarpa, Euphorbiameridensis, Euphorbia mertonii, Euphorbia mexiae, Euphorbiamicrocephala, Euphorbia microclada, Euphorbia micromera, Euphorbiamisella, Euphorbia missurica, Euphorbia montana, Euphorbia montereyana,Euphorbia multicaulis, Euphorbia multiformis, Euphorbia multinodis,Euphorbia multiseta, Euphorbia muscicola, Euphorbia neomexicana,Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia oaxacana,Euphorbia occidentalis, Euphorbia odontodemia, Euphorbia olivacea,Euphorbia olowaluana, Euphorbia opthalmica, Euphorbia ovata, Euphorbiapachypoda, Euphorbia pachyrhiza, Euphorbia padifolia, Euphorbia palmeri,Euphorbia paludicola, Euphorbia paralias, Euphorbia parciflora,Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana, Euphorbiapediculifera, Euphorbia peplidion, Euphorbia peploides, Euphorbiapeplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbia petaloidea,Euphorbia petaloidea, Euphorbia petrina, Euphorbia picachensis,Euphorbia pilosula, Euphorbia pilulifera, Euphorbia pinariona, Euphorbiapinetorum, Euphorbia pioniosperma, Euphorbia platysperma, Euphorbiaplicata, Euphorbia poeppigii, Euphorbia poliosperma, Euphorbiapolycarpa, Euphorbia polycnemioides, Euphorbia polyphylla, Euphorbiaportoricensis, Euphorbia portulacoides Euphorbia portulana, Euphorbiapreslii, Euphorbia prostrata, Euphorbia pteroneura, Euphorbiapycnanthema, Euphorbia ramosa, Euphorbia rapulum, Euphorbia remyi,Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis,Euphorbia robusta, Euphorbia romosa, Euphorbia rubida, Euphorbiarubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbiasaxatilis M. Bieb, Euphorbia schizoloba, Euphorbia sclerocyathium,Euphorbia scopulorum, Euphorbia senilis, Euphorbia serpyllifolia,Euphorbia serrula, Euphorbia setiloba Engelm, Euphorbia sonorae,Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerosperma,Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea,Euphorbia stellata, Euphorbia submammilaris, Euphorbia subpeltata,Euphorbia subpubens, Euphorbia subrenforme, Euphorbia subtrifoliata,Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides,Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli,Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii,Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor,Euphorbia troyana, Euphorbia tuerckheimii, Euphorbia turczaninowii,Euphorbia umbellulata, Euphorbia undulata, Euphorbia vermiformis,Euphorbia versicolor, Euphorbia villifera, Euphorbia violacea, Euphorbiawhitei, Euphorbia xanti Engelm, Euphorbia xylopoda Greenm., Euphorbiayayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica andEuphorbia zinniiflora.
 43. A method according to claim 41 wherein thespecies of Euphorbia is Euphorbia peplus.
 44. A method according toclaim 33 wherein the cancer is prostate cancer.
 45. A method accordingto any one of claims 33 to 44 wherein the chemical agent is coupled to atargeting agent.
 46. A method according to claim 45 wherein thetargeting agent targets a component of the immune system.
 47. A methodaccording to claim 46 wherein the targeting agent is an immunoglobulin.48. A method according to claim 47 wherein the immunoglobulin targets adendritic cell.
 49. A method according to claim 48 wherein theimmunoglobulin targets a B-or T-cell.
 50. A method according to claim 1or 33 wherein the chemical agent is a jatrophane or a derivative thereofor a pharmaceutically acceptable salt of these.
 51. A method accordingto claim 50 wherein said derivative is an ester derivative.
 52. A methodaccording to claim 50 wherein said derivative is an acetylatedderivative.
 53. A method according to claim 1 or 33 wherein saidchemical agent is a pepluane or a derivative thereof or apharmaceutically acceptable salt of these.
 54. A method according toclaim 53 wherein said derivative is an ester derivative.
 55. A methodaccording to claim 53 wherein said derivative is an acetylatedderivative.
 56. A method according to claim 1 or 33 wherein saidchemical agent is a paraliane or a derivative thereof or apharmaceutically acceptable salt of these.
 57. A method according toclaim 56 wherein said derivative is an ester derivative.
 58. A methodaccording to claim 56 wherein said derivative is an acetylatedderivative.
 59. A method according to claim 1 or 33 wherein saidcompound is an angeloyl-substituted ingenane or a derivative thereof ora pharmaceutically acceptable salt of these.
 60. A method according toclaim 59 wherein said derivative is an acetylated derivative.
 61. Amethod according to claim 59 wherein said jatrophane is of conformation2.
 62. A method according to claim 50 or 53 or 56 or 59 wherein thederivative comprises a substitution as represented in any one of generalformulae (I)-(VI).
 63. A method according to claim 1 or 33 wherein saidcompound is 5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane(pepluane) or a derivative thereof or a pharmaceutically acceptable saltof these.
 64. A method according to claim 63 wherein said derivative isan ester derivative.
 65. A method according to claim 1 or 33 whereinsaid compound is2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11E-dieneOatrophane 1) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 66. A method according to claim 65 wherein saidderivative is an ester derivative.
 67. A method according to claim 1 or33 wherein said compound is 2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxyjatropha-6(17),11E-diene (jatrophane 2) or a derivativethereof or a pharmaceutically acceptable salt of these.
 68. A methodaccording to claim 67 wherein said derivative is an ester derivative.69. A method according to claim 1 or 33 wherein said compound is2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxjatropha-6(17),11E-diene (jatrophane 3) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 70. A method according to claim 69 whereinsaid derivative is an ester derivative.
 71. A method according to claim1 or 33 wherein said compound is 2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxyatropha-6(17),11E-diene) (jatrophane 4) ora derivative thereof or a pharmaceutically acceptable salt of these. 72.A method according to claim 71 wherein said derivative is an esterderivative.
 73. A method according to claim 1 or 33 wherein saidcompound is2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(17),11E-diene(jatrophane 5) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 74. A method according to claim 73 wherein saidderivative is an ester derivative.
 75. A method according to claim 1 or33 wherein said compound is2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyatropha-6(17),11E-diene (jatrophane 6) or a derivative thereof or apharmaceutically acceptable salt of these.
 76. A method according toclaim 75 wherein said derivative is an ester derivative.
 77. A methodaccording to claim 1 or 33 wherein said compound is20-O-acetyl-ingenol-3-angelate or a derivative thereof or apharmaceutically acceptable salt of these.
 78. A method according toclaim 77 wherein said derivative is an ester derivative.
 79. A methodaccording to claim 1 or 33 or 63 or 65 or 67 or 69 or 71 or 73 or 75 or77 wherein said compound is provided in the form of a compositioncomprising a pharmaceutically- or cosmetically-acceptable carrier.
 80. Amethod for the treatment or prophylaxis of a subject with prostatecancer or a related condition or with the symptoms of prostate cancer,said method comprising the administration to said subject of asymptom-ameliorating effective amount of an angeloyl substitutedingenane or a chemical fraction or plant extract comprising same.
 81. Amethod for the treatment or prophylaxis of a subject with prostatecancer or a related condition or with the symptoms of prostate cancer,said method comprising the administration to said subject of asymptom-ameliorating effective amount of one or more ofingenol-3-angelate, 20-deoxy-ingenol-3-angelate and/or20-O-acetyl-ingenol-3-angelate or derivative thereof or apharmaceutically acceptable salt of these or a chemical fraction orplant extract comprising same.
 82. A method for the treatment orprophylaxis of prostate cancer or a related cancer in a subject, saidmethod comprising the simultaneous or sequential administration to saidsubject of a symptom-ameliorating effective amount of a chemical agentderived from a plant of the Euphorbiaceae family together with atherapeutic protocol or a symptom-ameliorating effective amount ofanother chemical agent or a physical agent.
 83. (amended) Use of achemical agent or derivative or chemical analog thereof as representedby any one of the present Formulae (I) to (V) or (VI) in the manufactureof a medicament for treatment and/or prophylaxis of prostate cancer or arelated condition in a subject.
 84. A chemical agent derived from aplant of the Euphorbiaceae family coupled to a targeting agent.
 85. Achemical agent according to claim 84 wherein said agent prior tocoupling is a compound of any of formulae (I)-(V) or (VI).
 86. Achemical agent according to claim 85 wherein said chemical agent isjatrophane.
 87. A chemical agent according to claim 86 wherein thechemical agent is jatrophane of conformation
 2. 88. A chemical agentaccording to claim 85 wherein said chemical agent prior to coupling is5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane) or aderivative thereof or a pharmaceutically acceptable salt of these.
 89. Achemical agent according to claim 88 wherein said derivative is an esterderivative.
 90. A chemical agent according to claim 85 wherein saidchemical agent prior to coupling is2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy- 14-oxojatropha-6(17),11E-diene(jatrophane 1) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 91. A chemical agent according to claim 90 wherein saidderivative is an ester derivative.
 92. A chemical agent according toclaim 85 wherein said chemical agent prior to coupling is2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxy-j atropha-6(17),11E-diene (jatrophane 2) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 93. A chemical agent according to claim 92wherein said derivative is an ester derivative.
 94. A chemical agentaccording to claim 85 wherein said chemical agent prior to coupling is2,5,1⁴-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxyjatropha-6(17),11E-diene (jatrophane 3) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 95. A cheinical agent according to claim 94wherein said derivative is an ester derivative.
 96. A chemical agentaccording to claim 85 wherein said chemical agent prior to coupling is2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-jatropha-6(17),11E-diene) ((jatrophane 4) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 97. A chemical agent according to claim 96wherein said derivative is an ester derivative.
 98. A chemical agentaccording to claim 85 wherein said chemical agent prior to coupling is2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxy-jatropha-6(17),11E-diene (jatrophane 5) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 99. A chemical agent according to claim 98wherein said derivative is an ester derivative.
 100. A chemical agentaccording to claim 85 wherein said chemical agent prior to coupling is2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),1E-diene (jatrophane 6) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 101. A chemical agent according to claim 100wherein said derivative is an ester derivative.
 102. A chemical agentaccording to claim 85 wherein said chemical agent prior to coupling is20-O-acetyl-ingenol-3-angelate or a derivative thereof or apharmaceutically acceptable salt of these.
 103. A chemcial agentaccording to claim 102 wherein said derivative is an ester derivative.104. A chemical agent according to any one of claims 84 to 103 whereinsaid chemical agent is provided in the form of a composition comprisinga pharmaceutically- or cosmetically-acceptable carrier.
 105. A chemicalagent according to any one of claims 84 to 103 wherein the targetingagent is a bone-seeking agent.
 106. A chemical agent according to claim105 wherein the bone-seeking agent is bisphosphonate.
 107. A chemicalagent according to claim 106 wherein the bisphosphonate is methylenedisphosphonate.
 108. A chemical agent according to any one of claims 84to 103 wherein the targeting agent is an antibody.
 109. A chemical agentaccording to claim 108 wherein the targeting agent is an antibody to aprostate-specific tumor marker.
 110. A chemical agent according to claim108 wherein the marker is prostate- specific antigen (PSA),prostate-specific membrane antigen (PMSA) or PSA receptor.
 111. Achemical agent according to claim 108 wherein the antibody is specificto a component of the immune system.
 112. A chemical agent according toclaim 111 wherein the immune system component is a dendritic cell, B- orT-cell.